AICAR induces AMPK-independent programmed necrosis in prostate cancer cells

Area of Science:

• Oncology
• Cell Biology
• Biochemistry

Background:

• AICAR (5-Aminoimidazole-4-carboxamide riboside) is an AMPK agonist with known cytotoxic effects on cancer cells.
• Its specific mechanisms in prostate cancer remain underexplored.
• Prostate cancer remains a significant global health concern requiring novel therapeutic strategies.

Purpose of the Study:

• To investigate the cytotoxic effects of AICAR on prostate cancer cells.
• To elucidate the underlying signaling pathways involved in AICAR-induced cell death.
• To determine if AICAR's effects are mediated by apoptosis or necrosis.

Main Methods:

• Prostate cancer cell lines (LNCaP, PC-3, PC-82) were treated with AICAR.
• Apoptosis and necrosis were assessed using specific assays.
• The role of AMPK, cyclophilin-D (CYPD), and reactive oxygen species (ROS) was investigated using inhibitors and shRNAs.
• Necrostatin-1, cyclosporin A, sanglifehrin A, N-acetylcysteine, and MnTBAP were utilized.

Main Results:

• AICAR predominantly induced programmed necrosis, not apoptosis, in prostate cancer cells.
• Necrostatin-1 significantly attenuated AICAR's cytotoxicity.
• Inhibition of mitochondrial protein CYPD, via inhibitors or shRNAs, markedly reduced AICAR-induced necrosis.
• AICAR-induced necrosis was independent of AMPK activation but required ROS production, as evidenced by ROS scavengers inhibiting the effect.

Conclusions:

• AICAR exhibits cytotoxicity in prostate cancer cells primarily through AMPK-independent programmed necrosis.
• Mitochondrial CYPD and ROS production are critical mediators of AICAR-induced necrosis.
• These findings provide mechanistic insights into AICAR's action and suggest potential therapeutic avenues for prostate cancer.