Sugars to signals: emerging roles of PAK1 in re-wiring glucose metabolism in cancers.

[INTRODUCTION] p21-activated kinase 1 (PAK1) is a critical serine/threonine kinase involved in regulating key cellular processes driving cancer progression. While PAK1 is well-known for its contributions to the hallmarks of cancer - such as sustained proliferation, evasion of apoptosis, and metastasis - emerging evidence highlights its pivotal role in cancer metabolism, particularly in orchestrating the Warburg effect.

[AREAS COVERED] This review focuses on the multifaceted influence of PAK1 in metabolic reprogramming, emphasizing both its direct and indirect regulation of aerobic glycolysis, a hallmark metabolic adaptation in tumor cells. We explore how PAK1 modulates signaling pathways and metabolic enzymes to shift glucose metabolism toward glycolysis, supporting the biosynthetic and energetic demands of rapidly proliferating cancer cells. By bridging oncogenic signaling and metabolic remodeling, PAK1 acts as a central integrator that facilitates tumor growth and survival. Elucidating the mechanistic links between PAK1 and the Warburg effect unveils novel opportunities for targeted cancer therapies aimed at disrupting metabolic vulnerabilities.

[EXPERT OPINION] An ideal biodegradable drug delivery system and an appropriately representative pre-clinical model exploiting the Warburg effect could enhance targeted delivery and therapeutic efficacy, and could help advance tumor targeted therapies in aggressive cancers like TNBC and pancreatic cancer.