The Role of PDE3A in Cancer.

1
Introduction
PDE3 is a cytosolic enzyme
that can hydrolyze cAMP and cGMP. It
is usually classified into two subtypes (PDE3A and PDE3B).
,
A pivotal study conducted in 1992 reported the complete cDNA sequence
of PDE3A, and numerous follow-up researches have demonstrated that
PDE3A exists in at least three isoform variants within cellular environments. These isoforms share an identical C-terminal
phosphodiesterase domain while differing significantly in their N-terminal
regulatory regions. Biochemical analyses
indicate that PDE3A exhibits a stronger binding affinity for cGMP
compared to cAMP; however, its maximum reaction rate (Vmax) toward
cAMP is approximately ten times higher than that toward cGMP.
,
This characteristic provides a mechanistic explanation for why cGMP
can effectively impede the PDE3A-catalyzed hydrolysis of cAMP. Experiments
utilizing truncated PDE3A mutants confirmed that the C-terminal domain
of PDE3A alone is competent enough to catalyze the hydrolysis of cAMP
and cGMP.

PDE3A is mainly found
in tissues such as platelets, heart, and
vascular smooth muscle, and can control the concentrations of the
two cyclic nucleotides by hydrolyzing them.
,
cAMP
and cGMP, as second messengers, can participate in signal transduction
in platelet activation, excitation-contraction
coupling in the heart, and growth of vascular
smooth muscle, thereby exerting their
functions. It has been well established that PDE3A modulates intracellular
concentrations of cAMP and cGMP, thereby regulating a series of vital
biological processes including oocyte maturation, muscle contraction,
and vascular dilation.
,
Pharmacological inhibition of
PDE3A’s phosphodiesterase activity has been shown to exert
multiple biological effects: it can interfere with oocyte maturation,
reduce platelet production, and elevate the risk of sudden cardiac
death in patients suffering from heart diseases. Next, we will discuss
the physiological and pathololgical functions of PDE3A in detail.

2
PDE3A in Normal Tissue
2.1
PDE3A and Cardiac Function
Research
found that PDE3A regulates the autonomous rhythm and myocardial contractile
function of cardiac pacemaker cells. In these cells, PDE3A works synergistically
with PDE4 to maintain basal cAMP levels and regulate the spontaneous
beating frequency. Dual inhibition of
PDE3A and PDE4 can significantly elevate cAMP concentrations, enhance
L-type calcium current (I(Ca,L)), and promote local Ca2+ release (LCRs), thereby accelerating diastolic depolarization
(DD) and increasing heart rate. This synergistic
effect has been demonstrated in the sinoatrial node of various species,
including rabbits and mice. Regarding
myocardial contractile function, PDE3A knockout (KO) mice exhibit
a significantly elevated basal heart rate, while PDE3B KO mice show
no difference compared to wild-type animals. The absence of a heart
rate response to the PDE3 inhibitor cilostamide in PDE3A KO mice further
suggests that PDE3A is the predominant PDE3 isoform in the heart,
responsible for regulating basal heart rate. Additionally, the cAMP-PDE activity in membrane preparations from
the hearts of PDE3A KO mice is reduced and not inhibited by cilostamide,
further supporting the dominant role of PDE3A in myocardial cAMP metabolism.

2.2
PDE3A and Platelets
PDE3A plays a
crucial role in platelet activation. Studies have shown that PDE3A
hydrolyzes cAMP to 5′-AMP, maintaining low cAMP levels within
platelets and thereby lowering the threshold for activation. In atherosclerotic conditions, oxidized low-density
lipoprotein (oxLDL) activates the Src/Syk/PKC signaling pathway through
the CD36 receptor, leading to sustained activation of PDE3A. Thrombin also activates PKC via protease-activated
receptors (PARs), which phosphorylate multiple serine residues, including
Ser298, on PDE3A, thereby enhancing its catalytic activity. These mechanisms collectively reduce cAMP levels,
diminishing the inhibitory effect of prostacyclin (PGI2) and promoting excessive platelet activation. In PDE3A KO mice,
basal cAMP levels in platelets are significantly elevated, rendering
them insensitive to PDE3 inhibitors, and they exhibit a marked antithrombotic
effect in a pulmonary thrombosis model. In contrast, PDE3B deficiency
does not produce this phenotype. These
findings underscore the central role of PDE3A in regulating platelet
function, highlighting it as a potential target for antiplatelet therapy.

2.3
PDE3A and Oocytes
PDE3A regulates
the activation and dormancy of primordial follicles. In the ovaries of neonatal mice, the coordinated upregulation
of PDE3A and ADCY3 maintains stable cAMP concentrations, providing
a molecular basis for the homeostasis of primordial follicles. Inhibition
of PDE3A effectively increases cAMP levels in oocytes, significantly
accelerating the activation of primordial follicles. Further studies
have demonstrated that elevated cAMP levels activate mTORC1 and PI3K
signaling through PKA, leading to phosphorylation of the downstream
factor rpS6 and the phosphorylation and translocation of the transcription
factor FOXO3a from the nucleus to the cytoplasm (CL-FOXO3a), thereby
driving follicular activation. This regulatory balance is essential
for maintaining the reproductive lifespan and health of females.

2.4
PDE3A in Pathology Diseases
2.4.1
PDE3A and Arrhythmias
The study
conducted by Alessandra Ghigo et al. highlighted that PDE3A dysfunction
is a key mechanism underlying catecholamine-sensitive arrhythmias.
In the PI3Kγ-deficient (PI3Kγ–/–) mouse model, PDE3A activity is significantly reduced,
leading to delayed cAMP clearance following β2-adrenergic
receptor (β2-AR) activation. This delay results in
excessive phosphorylation of PKA-mediated L-type calcium channels
(Cav1.2) and phospholamban, ultimately triggering spontaneous
calcium release events and ventricular arrhythmias. Further investigation revealed that PI3Kγ forms a
complex with PDE3A via its scaffold function, activating PDE3A through
PKA-mediated signaling. This interaction
limits local cAMP accumulation, thereby preventing calcium-dependent
arrhythmias. Consequently, PDE3A serves as a crucial effector molecule
in the PI3Kγ-mediated antiarrhythmia signaling pathway. PI3Kγ
couples PKA with PDE3A, precisely compartmentalizing and negatively
regulating the β2-AR/cAMP signal. Disruption of this mechanism represents a key molecular
basis for the development of arrhythmias.

2.4.2
PDE3A
and Chronic Heart Failure
A 2023 study revealed that the
interaction between PDE3A and SERCA2
is implicated in chronic heart failure (CHF). In this condition, impaired myocardial contraction is directly associated
with reduced activity of the sarcoplasmic reticulum calcium pump (SERCA2).
PDE3A binds directly to SERCA2 and inhibits its function. Functional
studies have demonstrated that disrupting this interaction with a
specific peptide, such as OptF, significantly enhances SERCA2 activity
and improves calcium handling in myocardial cells. These findings suggest that targeting the PDE3A-SERCA2
interaction may offer a novel therapeutic strategy for CHF.

2.4.3
PDE3A and Female Infertility
PDE3A
is implicated in female infertility. Studies have shown that deficiency
of the PDE3A gene (PDE3A–/–) results
in complete infertility in female mice. The absence of PDE3A leads to elevated cAMP levels in oocytes and
continuous activation of PKA. Activated PKA phosphorylates downstream
targets, such as Cdc25B and PlK1, which inhibit the activation of
the maturation-promoting factor (MPF). This disruption causes meiotic
division of oocytes to arrest at the germinal vesicle (GV) stage,
preventing further maturation and completion of fertilization.
,
In vitro studies have shown that inhibition of PKA can effectively
alleviate meiotic arrest and restore fertilization capacity. These findings suggest that PDE3A could serve
as a potential target for intervention in female contraception or
assisted reproductive technologies.
Beyond these well-documented
regulatory roles of PDE3A that are mediated by classic second messengers,
a growing body of research has uncovered cAMP- and cGMP-independent
functions of PDE3A in facilitating cancer cell apoptosis in recent
years (Figure
). Several
PDE3 enzyme inhibitors have been shown to exert cytotoxic effects
on cancer cells. This review examined the expression and regulation
of PDE3A in cancer cells, its role in cell signal transduction, and
its involvement in tumor initiation, progression, metastasis, and
chemotherapy resistance. Additionally, the study explored the inhibition
of PDE3A and its potential as a therapeutic target for cancer treatment.

3
Methods
3.1
Search Strategy
All the studies mentioning
PDE3A and its association with cancer were retrieved from PubMed.
The advanced search terms we used were: ((PDE3A) OR (phosphodiesterase
3A)) AND ((tumor) OR (cancer)). As of April 2, 2025, our search results
yielded 221 papers.

3.2
Screening Criteria
These articles
are classified into the following categories: 10 articles related
to breast cancer, among which 2 are highly relevant; 2 articles related
to bladder cancer, but not related to PDE3A; 4 articles related to
cervical cancer, among which 3 are highly relevant; 1 article related
to glioma, but related to NPP1; 3 articles related to lymphoma, with
little relevance; 1 article related to mucinous lipoma; 2 articles
related to esophageal cancer, with 1 being highly relevant; 3 articles
related to prostate cancer, all without relevance; 5 articles related
to bone tumors, with only 1 being highly relevant; 5 articles related
to ovarian cancer, with 1 being highly relevant; 8 articles related
to kidney cancer, with little relevance; 5 articles related to thyroid,
with 1 being highly relevant; 9 articles related to pancreatic cancer,
with 1 discussing pancreatic ductal carcinoma; 14 articles related
to colorectal cancer, mainly related to PDE3B; 7 articles related
to melanoma, with only 1 being relevant; 28 articles related to lung
cancer, with only 2 being relevant; 9 articles related to gastric
cancer, all irrelevant; 17 articles related to gastrointestinal stromal
tumors (GIST), with 7 having significant relevance; 27 articles related
to liver cancer, with 2 being highly relevant; 27 articles related
to vascular tumors, with only 1 being relevant; 1 article related
to gum cancer; 1 article related to hematological tumors.

4
Results and Discussion
4.1
The Expression of PDE3A
in Cancer
PDE3A expression is dysregulated in a spectrum
of human cancers,
with notable enrichment in GIST, hepatocellular
carcinoma (HCC), gingival squamous cell
carcinoma, breast cancer, human squamous carcinoma, ovarian carcinoma, myxoid
liposarcoma, and certain subtypes of
colorectal cancer. PDE3A has been most
extensively studied in GIST. Immunohistochemical
analysis of tissue microarrays has demonstrated PDE3A immunoreactivity
in 92% of KIT-positive tumors, including
both spindle and epithelioid subtypes as well as metastatic lesions.
This high expression is lineage-specific, as GIST originates from
interstitial cells of Cajal (ICC), where
PDE3A is constitutively expressed throughout development and plays
a role in ICC maturation. In PDE3A-deficient mice, ICC density is
halved, underscoring the protein’s essential role in the development
of this cell lineage and its derivative tumors.
Compared with
nonalcoholic steatohepatitis (NASH) and normal liver tissue, PDE3A
is one of the proteins upregulated in alcoholic hepatitis (AH). Since AH progresses to cirrhosis and HCC at
a higher rate than NASH, PDE3A overexpression may contribute to the
increased tumorigenic potential of AH-associated liver disease. Similarly,
in human gingival carcinoma, PDE3A expression is significantly elevated
in tumor tissues compared to normal gingiva, and higher enzyme activity
is observed in cases with lymph node metastasis, suggesting a correlation
between PDE3A levels and disease progression. Notably, PDE3A expression is not universal across all cancer types.
In colorectal cancer cell lines such as HT-29 and DLD-1, PDE3A mRNA
is undetectable, indicating tissue-specific regulation of its expression.
,

Studies have found that high expression of PDE3A in lung adenocarcinoma
(LUAD) is associated with better patient prognosis. Overexpression
of PDE3A can make A549/Cis cells more sensitive to cisplatin and enhance
cisplatin-induced caspase-3 activation (a marker of apoptosis), although
overexpression of PDE3A alone does not induce cell apoptosis. Additionally, high PDE3A expression is correlated
with favorable overall survival (OS, HR = 0.53, p < 0.0001) and progression-free survival (PFS, HR = 0.54, p < 0.001) in patients with LUAD (median OS: 136.33 vs
72 months; median PFS: 45.3 vs 19 months for high vs low expression).
In contrast, high PDE3A expression was associated with poorer OS (HR
= 1.56, p = 0.017) and PFS (HR = 1.83, p = 0.04) in patients with lung squamous cell carcinoma (LUSC).

PDE3A is also identified as a significantly
mutated gene in esophageal
small cell carcinoma (SCCE) and is upregulated
in breast cancer, where it associates with poor prognosis, metastasis,
and cancer stem cell (CSC) properties. In nonsmall cell lung cancer (NSCLC), PDE3A is downregulated via
hypermethylation in cisplatin-resistant cells, with subtype-specific
prognostic value (favorable in adenocarcinoma, unfavorable in squamous
cell carcinoma). Squamous cell carcinoma
(HeLa cells) shows selective overexpression of PDE3A and PDE2A, correlating
with sensitivity to PDE inhibitors.

It was pointed out that the expression level of PDE3A in AML cells
is higher than that in normal cells, and its high expression is associated
with worse event-free survival (EFS) in newly diagnosed AML patients. It was found that the PDE3A inhibitor anagrelide
(ANA) can significantly inhibit the proliferation of AML cells with
high PDE3A expression, while having little effect on cells with low
PDE3A expression. Moreover, ANA shows a synergistic effect with other
chemotherapeutic drugs in AML cells with high PDE3A expression, especially
the combination of ANA and idarubicin, which shows the most significant
synergistic effect. This synergistic effect inhibits the survival
of AML cells with high PDE3A expression through GSDME-mediated pyroptosis,
which is initiated by caspase-3 activation triggering GSDME cleavage.
In leukemia animal models with high PDE3A expression, the combination
treatment of ANA and IDA significantly reduced leukemia burden and
extended survival, indicating that this combination treatment is a
promising therapeutic strategy for high-PDE3A expression AML patients.
Additionally, analysis revealed that both PDE3A and Schlafen family
member 12 (SLFN12) are highly expressed in various cancers, particularly
in myxoid liposarcoma (MLPS). SLFN12
is a protein with RNase activity. Recent studies have revealed that
the interaction between PDE3A and SLFN12 plays a crucial role in tumorigenesis,
development, and targeted therapy, emerging as a research hotspot
in the field of cancer biology. Studies indicated that the coexpression
of PDE3A and SLFN12 can serve as a biomarker for screening cancer
patients sensitive to PDE3A modulators, offering a new therapeutic
direction for MLPS and other tumor subtypes lacking effective precision
treatment options.

4.2
The Regulation of PDE3A Expression in Cancer
4.2.1
DNA Mutation of PDE3A
A study conducted
whole-exome sequencing on 50 DNA samples from healthy Korean individuals
and identified five missense variants in PDE3A: D12N, Y497C, H504Q,
C707R, and A980 V. Comparing the catalytic activity of the PDE3A missense
variants with the wild-type revealed that all variant proteins had
reduced catalytic activity (33–53%; p <
0.0001). Additionally, cilostazol exhibited a more pronounced inhibitory
effect on PDE3A activity in the missense variants, particularly PDE3A
Y497C. In summary, individuals carrying the PDE3A Y497C variant may
have lower cAMP phosphodiesterase activity, which could lead to differences
in cAMP-mediated physiological functions among individuals.

Another research presents a comprehensive
genomic profiling of 55 SCCE patients via whole-exome sequencing,
ultradeep targeted sequencing, and copy number microarray assays.
The main results showed that eight significantly mutated genes were
identified, including known drivers (TP53, RB1, NOTCH1, FAT1, FBXW7)
and three novel esophageal cancer-related genes (PDE3A, PTPRM, CBLN2). Biallelic inactivation of TP53 and RB1, frequent
MYC family (MYC, MYCL1) amplifications, and widespread alterations
in the Wnt/β-catenin, cell cycle, and p53 pathways were observed.
Notably, 96.4% of patients harbored Wnt pathway alterations, and NOTCH
family mutations correlated with poorer OS. These findings uncover
key molecular drivers of SCCE, challenge the current SCLC-mimetic
treatment paradigm, and provide a foundation for developing precision
therapies.

4.2.2
DNA Methylation of PDE3A
F-M Tian
et al. investigates the role of PDE3A in cisplatin resistance of nonsmall
cell lung cancer (NSCLC) and its association with patient survival
found that PDE3A is hypermethylated in cisplatin resistant NSCLC and
is a modulator of chemotherapy response. By reanalyzing GEO data set GDS5247 and mining TCGA database, researchers
found that PDE3A is significantly downregulated in cisplatin-resistant
NSCLC cells (e.g., H460/Cis and A549/Cis) compared to parental cells.
This downregulation is attributed to DNA hypermethylation, as evidenced
by a negative correlation between PDE3A expression and methylation
levels in LUAD patients and restored PDE3A expression in A549/Cis
cells treated with the demethylating agent 5-AZA-dC. These findings
identify DNA hypermethylation-mediated PDE3A downregulation as a key
mechanism of cisplatin resistance in NSCLC, particularly adenocarcinoma.
PDE3A restoration enhances chemotherapy sensitivity, highlighting
its potential as a therapeutic target. Additionally, PDE3A expression
may serve as a subtype-specific prognostic biomarker for NSCLC, guiding
personalized treatment strategies.

4.2.3
DNA
Transcriptional Activation of PDE3A
Another article in 2017
revealed the role of SFPQ (a splicing factor
rich in proline and glutamate) in PDE3A gene expression, filling the
gap in the regulatory mechanism. In serum-induced
PDE3A expression, it was found that the binding of SFPQ to the upstream
regulatory region of PDE3A increased, indicating that SFPQ can regulate
PDE3A mRNA levels as a transcriptional activator of PDE3A. PDE3A expression
is reduced in cervical cancer cells. Overexpression of PDE3A can enhance
the sensitivity of Hela cells to DNMDP, achieving an anticancer effect.
Therefore, regulating PDE3A expression may effectively increase the
sensitivity of cervical cancer to specific anticancer drugs, providing
new ideas and directions for cancer treatment.
Another article
studied the oncogenic role of MYBL2 in melanoma to determine whether
it can serve as a diagnostic and therapeutic target for melanoma. MYBL2 often leads to poor prognosis and high
proliferation and metastatic capabilities of cancer cells. Through
RNA-Seq and ChIP-Seq analyses, PDE3A was identified as one of the
downstream target genes of MYBL2. It was found that the expression
of MYBL2 is positively correlated with the expression level of PDE3A,
and high expression of PDE3A in melanoma patients is significantly
associated with poor survival rates. This indicates that MYBL2 can
transcriptionally activate PDE3A, regulating its expression and promoting
the malignant progression of melanoma. Therefore, PDE3A can serve
as a potential biomarker for assessing melanoma prognosis.

4.2.4
Epigenetic Modification of PDE3A mRNA
Recent research
in NSCLC showed that FSCN1 (a RNA-binding protein)
may regulate the expression of PDE3A by affecting the alternative
splicing levels of mRNA precursors of NME4, NCOR2, and EEF1D, thereby
controlling the proliferation, migration, and invasion of cancer cells. Silencing FSCN1 in A549 cells can significantly
increased the expression level of PDE3A, which indicating that FSCN1
may inhibit the expression of PDE3A through some mechanism. Through
RNA immunoprecipitation (RIP) and RNA-seq analysis, researchers found
that FSCN1 can directly bind to the mRNA of PDE3A and may affect the
expression of PDE3A by regulating the splicing level of its precursor
mRNA. These findings revealed the potential
mechanism of PDE3A in lung cancer progression and the interaction
between FSCN1 and PDE3A, providing new perspectives and potential
targets for molecular diagnosis and targeted therapy of lung cancer.
A recent study showed that in cervical cancer, METTL3 targets PDE3A
through m6A modification and enhances the stability of PDE3A mRNA
through YTHDF3, thereby promoting PDE3A protein expression, which
in turn affects the proliferation and migration of cancer cells. The article suggests that the METTL3/YTHDF3/PDE3A
axis could be a potential clinical target for cervical cancer treatment.
S. Yasmeen et al. investigated miRNAs targeting PDE3A as potential
therapeutic targets for cerebral small vessel disease (CSVD), with
a focus on cerebral microvascular endothelial dysfunction. Using in silico analysis (TargetScan, miRWalk),
67 PDE3A-targeting miRNAs were identified, with 49 expressed in the
hCMEC/D3 human cerebral endothelial cell line. Coexpression meta-analysis
clustered these miRNAs into seven groups, with the top two clusters
(miR-221/miR-222 and miR-27a/miR-27b/miR-128) are linked to critical
pathways in vascular integrity, immune regulation, and neurogenesis
via KEGG analysis. Notably, hCMEC/D3 cells exclusively expressed PDE3A
(not PDE3B). Transfection experiments confirmed that miR-27a-3p and
miR-222–3p mimics significantly reduced PDE3A protein expression
compared to control group. These miRNAs are known to be associated
with CSVD risk factors (diabetes, hypertension), and can offer isoform-specific
modulation of PDE3A, thereby avoiding side effects of nonselective
PDE3 inhibitors like cilostazol. The findings highlight miR-27a-3p
and miR-222–3p as promising therapeutic candidates for CSVD
by targeting endothelial PDE3A to improve barrier function and cerebral
blood flow.

4.2.5
Post-Translational Modifications
of PDE3A
Protein
Mercedes et al. found that PDE3A binds to 14–3–3
proteins in response to PMA-induced phosphorylation of Ser428. Researchers found that PDE3A coimmunoprecipitates
with endogenous 14–3–3 proteins in a phosphorylation-dependent
manner, with PMA (a PKC activator) inducing maximal binding. Inhibitor
studies revealed PKC, not MAPK or SAPK2/p38, mediates this interaction.
MS/MS and phosphospecific antibodies identified five in vivo phosphorylation
sites on PDE3A, with Ser428 selectively phosphorylated by PMA and
dephosphorylated by DNA replication inhibitors (aphidicolin, mimosine),
correlating directly with 14–3–3 binding. Forskolin-induced
PKA phosphorylation of Ser312 did not promote 14–3–3
binding, demonstrating 14–3–3′s ability to discriminate
between phosphorylation sites. This study uncovers PKC-mediated Ser428
phosphorylation as the key trigger for PDE3A-14–3–3
interaction, highlighting multisite phosphorylation’s role
in regulating PDE3A function and its potential involvement in cytoskeletal
dynamics.

4.3
The Function of PDE3A in
Cancer
Functionally,
PDE3A contributes to oncogenesis through multiple mechanisms, involving
both catalytic and noncatalytic mechanisms (Figure
). As a cyclic nucleotide hydrolase, PDE3A
modulates intracellular cAMP levels to regulate cell proliferation,
apoptosis, motility and so on. Beyond its enzymatic activity, a growing
body of research is investigating the nonhydrolytic function of PDE3A,
exerting noncatalytic oncogenic effects through protein–protein
interactions, most notably with SLFN12. The PDE3A-SLFN12 complex,
induced by small molecules such as DNMDP and OPB-171775, triggers
SLFN12-mediated RNase activity, leading to selective cytotoxicity
in cancer cells coexpressing both proteins, creating a unique dependency
that can be exploited therapeutically. In addition, we have summarized
all oncology studies of PDE3A and their related findings in Table
, in order to provide
a more comprehensive understanding of the role of PDE3A in the development
and progression of various cancers, as well as its therapeutic potential.
Next, we will describe the carcinogenic role of PDE3A in various tumors
based on different phenotypes.

4.4
PDE3A and Cell Proliferation
PDE3A
regulates the growth of vascular smooth muscle cells (VSMCs) through
two complementary pathways: PKA-catalyzed inhibitory phosphorylation
of Raf-1 leads to suppression of MAPK signaling and PKA/CREB-mediated
induction of p21, resulting in G0/G1 cell cycle
arrest, as well as increased accumulation of p53, MKP-1, p21, and
WIP1, inhibiting the progression of the cell cycle from G1 to S. These mechanisms collectively
significantly reduce DNA synthesis and cell proliferation in VSMCs,
providing a potential therapeutic target for preventing vascular diseases
(such as atherosclerosis, vascular restenosis) and vascular tumors.

4.5
PDE3A-SLFN12 Interaction and Cell Death
4.5.1
Cytotoxic Effects and Molecular Mechanisms
Mediated by the PDE3A-SLFN12 Interaction
The interaction
between PDE3A and SLFN12 can specifically induce the death of cancer
cells with high coexpression of both proteins. Studies have shown
that SLFN12 inherently possesses RNase activity, and its binding to
PDE3A remarkably enhances this nuclease activity, which serves as
the core driver of the cytotoxic response in cancer cells.
−

Further investigations revealed that the formation of the PDE3A-SLFN12
complex triggers the dephosphorylation of SLFN12 (Ser368 and Ser573),
which not only increases the protein stability of SLFN12 but also
enhances its rRNA degradation activity, ultimately leading to cancer
cell death by disrupting ribosomal function and protein synthesis. In addition, the elevated level of SLFN12 binds
to ribosomes, thereby preventing the recruitment of signal recognition
particles (SRPs) and ultimately inhibiting the protein translation
process of Bcl-2 and Mcl-1, which in turn triggers cell apoptosis. The sensitivity of cytotoxic effect is strictly
dependent on the coexpression levels of PDE3A and SLFN12. Among 766
cancer cell lines, the sensitivity to DNMDP was positively correlated
with PDE3A expression, and SLFN12 coexpression was a necessary condition
for maintaining this sensitivity. Knockdown of either gene alone resulted
in the development of drug resistance in cancer cells. Furthermore, PDE3B can also interact with SLFN12
and support DNMDP sensitivity in the absence of PDE3A, suggesting
a certain degree of cross-reactivity among family members in this
interaction mechanism.

4.5.2
Induction Mechanism of the PDE3A-SLFN12
Interaction
The catalytic domain of PDE3A can bind to the
C-terminal α-helix of SLFN12 to form a heterotetrameric complex,
and small molecules such as DNMDP can act as “molecular glues”
to further stabilize this interaction. Other known compounds of the “molecular glue” such
as BRD9500, estradiol, anagrelide, nauclefine, and a variety of progesterone
receptor agonists
,,,−

(Figure
). Notably, the catalytic activity of PDE3A
is not a necessary condition for complex formation; however, the complete
expression of its catalytic domain is crucial for DNMDP binding and
complex assembly. Mutations in the active site will lead to the loss
of the compound’s binding ability, thereby blocking the occurrence
of the interaction.
,
In addition, the cochaperone
protein AIP has been confirmed to be an essential factor for the formation
of the PDE3A-SLFN12 complex. CRISPR screening results showed that
AIP deficiency significantly affect the DNMDP-induced PDE3A-SLFN12
interaction and subsequent cellular responses.

4.6
PDE3A and Metastasis and
Invasion
PDE3A plays a crucial role in the lymph node metastasis
of gingival
cancer. The background of the study is
based on the key role of PDE in intracellular signal transduction,
which regulates the intracellular signaling process by hydrolyzing
cAMP and cGMP. Therefore, the researchers analyzed the PDE and cAMP
activities in lymph node-negative (N(−)) and lymph node-positive
(N­(+)) patients with gingival cancer, and detected the expression
level of PDE3A using immunohistochemical methods. The results showed
that there were significant differences in PDE activity between the
N(−) group and the N­(+) group compared to the normal control
group. The PDE activity of the N­(+) group was more significantly different
from that of the control group (p = 0.0156), and
the difference between the N(−) group and the control group
was also statistically significant (p = 0.0433).
This indicated that changes in PDE activity may be related to the
invasion and lymph node metastasis of gingival cancer. In addition,
the immunohistochemical analysis of PDE3A also showed a significant
difference between the N(−) group and the N­(+) group (p = 0.0397), which further supports the important role of
PDE3A in the progression of gingival cancer.
Furthermore, PDE3A
promotes the translocation of CCDC88A from the cytoplasm to the nucleus,
thereby promoting the invasive metastasis cascade of breast cancer.
The selective PDE3A inhibitor cilostazol significantly inhibited the
growth of breast tumors and reduced lung metastasis in xenografted
breast cancer models, with minimal toxicity.

Another article studied the process by which ALDOA coordinates
PDE3A through the β-catenin/ID3 axis to promote cancer metastasis
and M2 macrophage polarization in lung cancer with EGFR mutations. It was found that in lung cancer patients with
EGFR mutations, the expression of ALDOA is abnormal, leading to dysfunction
and affecting related metabolic processes. Through multiomics analysis
(including transcriptomics, proteomics, and pulldown experiments),
a significant correlation was found between PDE3A and ALDOA, and they
affect the polarization of M2 macrophages through β-catenin
and its downstream ID3. M2 macrophages are a subpopulation of cells
with immunosuppressive characteristics that play an important role
in the tumor microenvironment, promoting tumor progression and metastasis.
Additionally, it was found that the PDE3A inhibitor trequinsin can
reduce the polarization state of M2 macrophages in lung cancer cell
lines with EGFR mutations and decrease cell migration, invasion, and
metastasis.
It was reported that PDE3A was significantly correlated
with the
OS of HCC patients and association with vascular invasion. This study used targeted next-generation sequencing
(tNGS) with a 603-cancer-gene panel to analyze 232 HCC and 22 intrahepatic
cholangiocarcinoma patients, including 47 unresectable/metastatic
HCC patients treated with anti-PD-1 plus bevacizumab. Results showed
PDE3A, LDLR, and FOXO1 alterations are linked to HCC vascular invasion,
and PDE3A can serve as a novel biomarker for HCC progression, recurrence,
and response to immunotherapy.
From these results, it can be
inferred that PDE3A may affect intracellular
signaling by regulating cAMP levels, thereby influencing the growth,
differentiation, and metastasis of cancer cells, especially in patients
with lymph node metastasis. Therefore, PDE3A is not only a potential
biomarker that can be used to assess the invasiveness and prognosis
of cancer but also a potential therapeutic target.

4.7
PDE3A and Cancer Stemness
Na Hao
et al. showed that PDE3A can act as a mediator of cancer stem cells­(CSCs),
making breast cancer patients prone to metastasis. It was found that
PDE3A inhibits the cAMP/PKA-induced inflammatory nuclear factor NF-κB
signaling pathway, promoting the expression of the stem cell marker
OCT4. Therefore, PDE3A is a potential
therapeutic target for advanced breast cancer.
A team of researchers
discovered that PDE3A is closely related to the characteristics of
CSCs in pancreatic ductal adenocarcinoma (PDAC). PDE3A is overexpressed in CD44+ cells of PDAC, and CD44
is a key marker of CSCs. This indicated that PDE3A may play an important
role in maintaining the characteristics of CSCs. Through immunofluorescence
staining and Western blotting, the study further confirmed the positive
correlation between PDE3A and CD44 expression, suggesting that the
high expression of PDE3A may affect the self-renewal, proliferation,
and survival characteristics of CSCs by regulating the expression
of CD44 or its related signaling pathways.
Furthermore, the
study also found that the inhibitor of PDE3A could
significantly enhance the inhibitory effect of EGCG (epicatechin gallate)
on CSCs. This combined treatment significantly weakened the characteristics
of CSCs by inhibiting the FOXO3 and CD44 axis. FOXO3 is a key transcription
factor closely related to the self-renewal and survival of CSCs, while
CD44 is an important marker of CSCs. The combined use of PDE3A inhibitor
and EGCG could significantly increase the intracellular cGMP level,
thereby regulating downstream signaling pathways to inhibit the characteristics
of CSCs. This combination treatment strategy
provides a new idea and direction for pancreatic cancer treatment.

4.8
PDE3A and TAM Cell in Tumor Microenvironment
Except the ALDOA coordinates PDE3A through the β-catenin/ID3
axis to promote M2 macrophage polarization in lung cancer with EGFR
mutations, another study reported that PDE3A plays an important regulatory
role in the M2 polarization of tumor-associated macrophages (TAMs)
mediated by ETV1 and the pathological progression of GIST. The results showed a positive correlation between
PDE3A and ETV1 and M2 polarization. Overexpression of PDE3A can reverse
the inhibitory effect of ETV1 knockdown. This indicated that regulating
the expression of PDE3A can affect the function of ETV1, thereby influencing
the polarization state of TAMs and the biological behavior of GIST
cells. This finding suggests that inhibiting ETV1 or regulating the
expression of PDE3A to intervene in TAM polarization, thereby inhibiting
the malignant progression of GIST, which providing a new potential
target for GIST treatment.

4.9
PDE3A and Therapeutic Resistance
As mentioned earlier, PDE3A is downregulated in cisplatin-resistant
NSCLC cells, and forced expression of PDE3A can enhance the sensitivity
of A549 cells to cisplatin, indicating that PDE3A may play an important
role in chemotherapy resistance of lung cancer cells.

Studies confirmed a novel molecular glue OPB-171775-regulating
the PDE3A-SLFN12 interaction – could effectively inhibit tumor
growth in tyrosine kinase inhibitor (TKI)-resistant and other GIST
subtypes. As a novel non-TKI agent, OPB-171775 represents a promising
candidate for treating TKI-resistant GIST. Mechanically, OPB-171775
binds to PDE3A, inducing PDE3A-SLFN12 complex formation; this stabilizes
SLFN12, preventing its proteasomal degradation and promoting intracellular
accumulation. SLFN12 exerts RNase activity to target tRNA, causing
tRNA dysfunction/degradation and subsequent global protein synthesis
inhibition. This triggers cellular stress, activating the GCN2 signaling
pathway and ultimately leading to cell cycle arrest and death. Verified
in vitro, this mechanism exhibits potent antitumor effects in GIST
patient-derived xenograft (PDX) modelsregardless of KIT mutation
status.

Additionally, other studies
have shown that PDE3A inhibitors can
weaken the activity of GIST cells. Therefore,
researcher continued to study that the PDE3A inhibitor cilostazol
can enhance the inhibitory effect of imatinib on GIST cells, showing
a synergistic effect in both imatinib-sensitive GIST882 cell lines
and imatinib-resistant GIST48 cell lines. Cilostazol induces the nuclear
exclusion of YAP through a cAMP-independent mechanism, thereby inactivating
it. Moreover, the YAP/TEAD interaction inhibitor verteporfin can significantly
reduce the survival rate of GIST882 and GIST48 cells, further emphasizing
the potential application value of PDE3A or YAP-targeted drugs in
combination therapy to overcome GIST resistance.

4.10
PDE3A and Tumor Metabolism
Researchers
used normal human osteoblasts (NHOst) and SaOS-2 osteosarcoma cells
for experiments. The cells were cultured in specific media and treated
under certain conditions. The types and subtypes of PDE were then
identified. It was found that PDE3A is expressed and functional in
NHOst cells, regulating cAMP levels through hydrolysis and significantly
affecting cAMP accumulation stimulated by PGE2. In SaOS-2 cells, although
PDE3A mRNA was detected, its activity was not, indicating that PDE3A
may not be functional in these cells. The difference in PDE3A activity
may be related to bone metabolism and the biological characteristics
of bone tumors, providing important clues for understanding the role
of phosphodiesterase inhibitors in bone metabolism.

4.11
PDE3A and Tumor Immunology
As mentioned
earlier, PDE3A was a novel genetic alterations in liver cancer distinguish
distinct clinical outcomes and combination immunotherapy responses. The study performed comprehensive genomic profiling
of 232 HCC and 22 intrahepatic cholangiocarcinoma patients using targeted
next-generation sequencing (tNGS) with a 603-cancer-gene panel, focusing
on 47 unresectable/metastatic HCC patients treated with anti-PD-1
plus bevacizumab. In immunotherapy response, high tumor mutational
burden (TMB), PTPRZ1 alterations, and cell cycle-related alterations
are associated with higher objective response rates (ORR) and better
PFS, whereas KMT2D alterations are correlated with inferior PFS. This
study uncovers subtype-specific genomic drivers, identifies novel
prognostic biomarkers for liver cancer progression and recurrence,
and provides predictive genetic markers for anti-PD-1 plus bevacizumab
response, laying the groundwork for personalized clinical management.

4.12
PDE3A Inhibition and as Cancer Target
The distinctive expression pattern and functional roles of PDE3A
make it an attractive therapeutic target. Several strategies have
been explored, including direct inhibition of PDE3A catalytic activity,
disruption of PDE3A-SLFN12 interaction, and combination therapy with
existing anticancer agents.
Cilostazol, a clinically approved
PDE3 inhibitor, has shown promising preclinical efficacy in GIST,
reducing cell viability and synergizing with imatinib (combination
index CI50 = 0.15). This synergism
allows for dose reduction of both drugs, potentially minimizing adverse
effects associated with high-dose imatinib. In GIST xenograft models,
cilostazol monotherapy inhibits tumor growth, and its combination
with imatinib results in enhanced antitumor activity.

In squamous cell carcinoma, PDE3A is overexpressed
alongside PDE2A,
and PDE3A inhibition disrupts the cAMP-PKA signaling pathway linked
to ERK and AKT, triggering apoptotic cell death. PDE3A also contributes to imatinib resistance in GIST by
modulating the YAP pathway; its inhibition induces YAP nuclear exclusion,
overcoming treatment resistance. Additionally, novel pyridine derivatives
demonstrate that PDE3A inhibition correlates directly with cytotoxicity
in MCF-7 and HeLa cells, validating its role as a driver of tumor
growth.

Its noncatalytic functionforming
a cytotoxic PDE3A-SLFN12
complexinduces apoptosis, and noncatalytic targeting of PDE3A-SLFN12
through molecular glue compounds represents a novel therapeutic approach.
To date, various PDE3A modulators have been confirmed to exert anticancer
activity by promoting the PDE3A-SLFN12 interaction.
,,,−

OPB-171775, a small molecule that induces PDE3A-SLFN12 complex formation,
exhibits potent efficacy against GIST patient-derived xenografts (PDX)
regardless of KIT mutation status, including imatinib-resistant models.
This agent acts by stabilizing SLFN12, leading to ribosomal stress,
GCN2 pathway activation, and ultimately cell death. In vivo studies
demonstrate that OPB-171775 induces tumor regression in GIST PDX models
and achieves complete tumor eradication when combined with imatinib.
Similarly, DNMDP selectively kills PDE3A/SLFN12-coexpressing cancer
cells, with an IC50 of 27 nM in GIST882 cells, validating
the therapeutic potential of this interaction.

4.13
Application Prospects in Tumor Therapy
The interaction
between PDE3A and SLFN12 provides a novel target
and strategy for precision tumor therapy. Clinical sample analysis
revealed that both PDE3A and SLFN12 are highly expressed in MLPS,
particularly in high-grade tumors. MLPS cell lines with coexpression
of these two genes exhibit high sensitivity to PDE3A modulators. This
finding indicates that the coexpression of PDE3A and SLFN12 can serve
as a biomarker for screening cancer patients sensitive to PDE3A modulators,
offering a new therapeutic direction for MLPS and other tumor subtypes
lacking effective precision treatment options. Such compounds hold great potential for development as
novel targeted anticancer drugs, especially for tumor subtypes with
high PDE3A and SLFN12 coexpression.
Anagrelide, another PDE3
inhibitor approved for thrombocythemia, has shown efficacy in GIST
xenograft models, including those harboring KIT exon 9 mutations that
require high-dose imatinib. In preclinical studies, anagrelide reduced
tumor volume by 68% in KIT exon 9 mutant GIST models, outperforming
imatinib at standard doses. This suggests that PDE3A inhibitors may
provide an alternative treatment option for patients with imatinib-intolerant
or resistant disease.
Despite these promising findings, several
challenges remain in
translating PDE3A-targeted therapy to clinical practice. First, the
tissue-specific expression of PDE3A requires robust biomarkers to
identify patients most likely to benefit from treatment. Coexpression
of PDE3A and SLFN12 has emerged as a predictive biomarker for response
to molecular glue compounds, as demonstrated by the fact that only
double-positive cancer cells are sensitive to OPB-171775 and DNMDP. Second, potential off-target effects of PDE3
inhibitors, particularly on cardiovascular function, require careful
monitoring in clinical trials. However, the dose reduction enabled
by combination therapy may mitigate these risks.
Future research
directions should focus on expanding the understanding
of PDE3A’s role in additional cancer types, elucidating the
molecular mechanisms underlying its oncogenic functions, especially
functions other than hydrolysis and optimizing therapeutic strategies.
For instance, the role of PDE3A in succinate dehydrogenase (SDH)-deficient
GIST, a subtype with no effective targeted therapies, warrants investigation
given the coexpression of PDE3A and SLFN12 in diverse GIST histologies.
Additionally, further characterization of PDE3A isoforms and their
interactions with other signaling molecules may reveal novel therapeutic
vulnerabilities.
In conclusion, PDE3A has emerged as a key mediator
of cancer development,
with dysregulated expression and function observed in multiple cancer
types. Its dual role as a cyclic nucleotide regulator and a molecular
scaffold for oncogenic protein interactions provides unique opportunities
for targeted therapy. Preclinical studies demonstrate the efficacy
of PDE3A inhibitors and molecular glue compounds, either alone or
in combination with existing agents, highlighting their potential
to address unmet clinical needs in cancer treatment. With continued
translational research, PDE3A-targeted therapies may soon become a
valuable addition to the oncology armamentarium.