IR-B deficiency and fatty acid dysregulation accelerate prostate cancer progression via PI3K/AKT signaling

ABSTRACT The insulin receptor (IR) is markedly overexpressed in both human and mouse prostate cancer, with a significant elevation in the IR-A/IR-B ratio across patient tissues, cell lines, and Hi-Myc mouse prostates. To elucidate the role of IR-B in prostate tumorigenesis, we generated a prostate-specific IR-B knockout (KO) mouse model using Pbsn-Cre –driven recombination. Prostate-restricted loss of IR-B was confirmed at the transcript level and did not affect other tissues. Crossing these mice with Hi-Myc transgenics revealed that IR-B deficiency promotes accelerated progression to invasive adenocarcinoma, characterized by enhanced cellular proliferation and atypical histopathology. Transcriptomic and metabolomic profiling of dorsolateral prostate lobes demonstrated activation of PI3K/AKT and mTOR signaling, along with upregulation of IRS1/2/4 and IGF2. Metabolite analyses indicated elevated fatty acid levels and enhanced lipolysis pathways, implicating metabolic reprogramming in tumor progression. Notably, glucose and lipid metabolism genes, including GLUT1, GLUT12, FASN, and GPR120, were upregulated, accompanied by an increased BCL2/BAX ratio, suggesting apoptosis inhibition. Functional studies further revealed opposing roles of dietary fatty acids: ω-3 polyunsaturated fatty acids (EPA, DHA) suppressed prostate cancer cell survival, proliferation, and PI3K/AKT signaling while promoting apoptosis, whereas ω-6 fatty acid (arachidonic acid) exerted pro-tumorigenic, anti-apoptotic effects. Collectively, these findings identify IR-B loss as a driver of metabolic and signaling reprogramming that accelerates prostate tumorigenesis, while highlighting ω-3 fatty acids as potential modulators counteracting IR-B-deficient prostate cancer progression.