Synthetic Lethal Metabolic Targeting of Androgen-Deprived Prostate Cancer Cells with Metformin

Area of Science:

• Oncology
• Cell Biology
• Pharmacology

Background:

• Androgen-deprivation therapy (ADT) is a standard treatment for prostate cancer.
• ADT can induce senescence in prostate cancer cells, leading to cell-cycle arrest but continued cell viability.
• Understanding the mechanisms of ADT-induced senescence is crucial for developing more effective therapies.

Purpose of the Study:

• To investigate the mechanisms of senescence in prostate cancer cells treated with ADT.
• To determine if metformin, an antidiabetic drug, synergizes with ADT to enhance prostate cancer cell death.
• To evaluate the efficacy of combining ADT and metformin both in vitro and in vivo.

Main Methods:

• Prostate cancer cells were exposed to ADT to induce senescence.
• Senescence markers (p16INK4a, p27kip2) and signaling pathways (PI3K/AKT, AMPK, mTORC1) were analyzed.
• The expression of antiapoptotic protein XIAP was measured.
• Metformin was administered in combination with ADT in vitro and in vivo models.
• Tumor growth was assessed in patient-derived xenograft models.

Main Results:

• Long-term ADT exposure induced senescence, characterized by p16INK4a and/or p27kip2 induction.
• ADT led to PI3K/AKT activation, AMPK inactivation, mTORC1 activation, and increased XIAP expression.
• Combining metformin with ADT induced apoptosis and reduced senescent cell numbers in vitro.
• Metformin attenuated mTOR activation and inhibited tumor growth in vivo xenograft models.

Conclusions:

• ADT induces senescence through specific molecular pathways in prostate cancer cells.
• Metformin synergizes with ADT to promote apoptosis and inhibit tumor progression.
• Combining ADT and metformin presents a promising therapeutic strategy for eliminating persistent prostate cancer cells.