A novel direct activator of AMPK inhibits prostate cancer growth by blocking lipogenesis

Area of Science:

• Oncology
• Metabolic pathways
• Cellular signaling

Background:

• Prostate cancer (PCa) often exhibits increased lipogenesis and mTORC1 pathway activation.
• 5'AMP-activated kinase (AMPK) is a key regulator of cellular metabolism and growth, making it a potential therapeutic target for PCa.
• The sufficiency of AMPK activation in blocking cancer cell proliferation requires further investigation.

Purpose of the Study:

• To investigate the therapeutic potential of direct AMPK activation in prostate cancer.
• To identify specific AMPK activators for PCa treatment.
• To elucidate the mechanisms underlying AMPK-mediated inhibition of PCa growth.

Main Methods:

• Small molecule screening to identify a direct AMPK activator (MT 63-78).
• In vitro studies using androgen-sensitive and castration-resistant PCa (CRPC) cell models.
• In vivo studies in PCa models.
• Analysis of lipogenesis and mTORC1 pathway activity.
• Combination studies with androgen receptor (AR) signaling inhibitors.

Main Results:

• MT 63-78, a direct AMPK activator, was identified.
• Direct AMPK activation inhibited PCa cell growth, induced mitotic arrest, and apoptosis in vitro.
• AMPK activation reduced PCa tumor growth in vivo.
• Loss of AMPK catalytic subunits promoted PCa development.
• AMPK-mediated PCa growth inhibition was primarily driven by suppression of de novo lipogenesis, independent of mTORC1 blockade.
• MT 63-78 enhanced the efficacy of AR signaling inhibitors (MDV3100, abiraterone) in CRPC models.

Conclusions:

• Direct AMPK activation is sufficient to inhibit prostate cancer cell growth and tumor development.
• Suppression of de novo lipogenesis is the key mechanism for AMPK-driven PCa growth inhibition.
• AMPK represents a promising therapeutic target for lipogenesis-driven prostate cancers, especially in combination with AR signaling inhibitors for CRPC treatment.