Exploiting Metabolic Reprogramming and Its Therapeutic Vulnerabilities in Prostate Cancer

Prostate cancer is a metabolically distinct malignancy as it exhibits strong flexibility in how it uses energy and perform physiological processes. In contrast to many solid tumors which mostly depend on aerobic glycolysis, the primary prostate cancer cells still depend mainly on oxidative phosphorylation and tricarboxylic acid (TCA) cycle for energy supply. This unique metabolic pattern is mainly controlled by androgen receptor signaling and also affected by mitochondrial functions and zinc level inside the cells. When the disease goes into advanced stage, especially castration-resistant prostate cancer (CRPC), the tumor cells change their energy system toward glycolytic and lipogenic ways to support hyperactive cell cycle, therapy resistance, and metastasis. This review gives a detailed discussion about metabolic reprogramming in prostate cancer with focus on glycolysis, mitochondrial dysfunction, and dysregulated lipid and cholesterol metabolism. Key enzymes, transporters and transcription factors, such as GLUT1, HK2, PFK1, PKM2, LDHA, PDK, FABP5, ACLY, ACAC, FASN, SREBPs and LXRs are discussed as important players of tumor bioenergetics , and as possible drug targets. Especially lipid metabolism has shown strong relation with CRPC aggressiveness, which is promoted by androgen receptor-controlled increase of lipogenic enzymes and fatty acid transport process. Interaction between metabolic pathways and oncogenic signaling like PI3K/AKT/mTOR makes the situation more complex. The review also covers new therapeutic strategies which make use of these metabolic vulnerabilities, including small molecule inhibitors, natural substances, and combination treatments. Better understanding of metabolic reprogramming of prostate cancer at different disease stages can help in creating more specific therapies to overcome resistance and improve clinical outcomes.