Deciphering 14-3-3β-mediated phosphorylated alterations of cancer-related proteome in cisplatin resistance of gastric cancer.

Cisplatin (CDDP) resistance is a major obstacle in the management of advanced and recurrent gastric cancer (GC). An in-depth analysis of signaling pathways involved in GC cell phosphorylation could help to identify critical pathways linked to CDDP resistance. Our research aimed to investigate the molecular mechanisms and clinical implications of the role of 14-3-3β in GC CDDP resistance. We established an AGS cell line that was resistant to CDDP, and used this, along with AGS and HGC-27 cell lines, as well as subcutaneous xenografts in nude mice, to create in vitro and in vivo models for our functional experiments. To highlight the clinical significance, we also examined a cohort of 127 gastric cancer patients who underwent treatment with platinum drugs. The results indicated that the proteome regulated by 14-3-3β, along with its phosphorylated alterations, may contribute towards CDDP resistance in GC cells. It is noteworthy that 14-3-3β governs a distinct phosphorylation modification system by regulating various tumor-associated molecules, such as EGFR, Akt, MEK1, and NFκB-p65. Concurrently, upregulated 14-3-3β expression induced the phosphorylation of Hsp90B, thus facilitating CDDP resistance. Consequently, silencing 14-3-3β significantly improved CDDP sensitivity in vivo. An immune-histochemistry panel further disclosed that elevated expression of both 14-3-3β and p-Hsp90B correlated with worse survival, compared to all other combinations observed. Our study suggests that 14-3-3β modulates the phosphorylated alterations of the cancer-related proteome. Unveiling the role of the 14-3-3β/Hsp90B pathway in GC CDDP resistance implies it could serve as a potential therapeutic target for treating CDDP-resistant GC patients.