AICAR induces AMPK-independent programmed necrosis in prostate cancer cells.
AICAR (5-Aminoimidazole-4-carboxamide riboside or acadesine) is an AMP-activated protein kinase (AMPK) agonist, which induces cytotoxic effect to several cancer cells. Its potential activity in prostate cancer cells and the underlying signaling mechanisms have not been extensively studied. Here, we showed that AICAR primarily induced programmed necrosis, but not apoptosis, in prostate cancer cells (LNCaP, PC-3 and PC-82 lines). AICAR's cytotoxicity to prostate cancer cells was largely attenuated by the necrosis inhibitor necrostatin-1. Mitochondrial protein cyclophilin-D (CYPD) is required for AICAR-induced programmed necrosis. CYPD inhibitors (cyclosporin A and sanglifehrin A) as well as CYPD shRNAs dramatically attenuated AICAR-induced prostate cancer cell necrosis and cytotoxicity. Notably, AICAR-induced cell necrosis appeared independent of AMPK, yet requiring reactive oxygen species (ROS) production. ROS scavengers (N-acetylcysteine and MnTBAP), but not AMPKα shRNAs, largely inhibited prostate cancer cell necrosis and cytotoxicity by AICAR. In summary, the results of the present study demonstrate mechanistic evidences that AMPK-independent programmed necrosis contributes to AICAR's cytotoxicity in prostate cancer cells.
Department of Urology, Jinan Central Hospital Affiliated to Shandong University, Jinan, Shandong Province 250013, China.
Feng
F
Guo
Department of Urology, Jinan Central Hospital Affiliated to Shandong University, Jinan, Shandong Province 250013, China.
Shuang-Qing
SQ
Liu
Department of Urology, Jinan Central Hospital Affiliated to Shandong University, Jinan, Shandong Province 250013, China.
Xing-Hua
XH
Gao
Department of Urology, Jinan Central Hospital Affiliated to Shandong University, Jinan, Shandong Province 250013, China. Electronic address: longyang_zhang@yeah.net.
Long-Yang
LY
Zhang
D055372:AMP-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D000620:Aminoimidazole Carboxamide / Q000008:administration & dosage / Q000031:analogs & derivatives*; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008297:Male; D009336:Necrosis / Q000473:pathology; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D012265:Ribonucleotides / Q000008:administration & dosage*; D016896:Treatment Outcome
D017382:Reactive Oxygen Species; D012265:Ribonucleotides; D000620:Aminoimidazole Carboxamide; D055372:AMP-Activated Protein Kinases; C031143:AICA ribonucleotide
AICAR; AMPK; Cyclophilin-D; Programmed necrosis; Prostate cancer