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.
Biochemical and biophysical research communications. 2016 Apr 18 [Epub ahead of print]
Feng Guo, Shuang-Qing Liu, Xing-Hua Gao, Long-Yang Zhang
Department of Urology, Jinan Central Hospital Affiliated to Shandong University, Jinan, Shandong Province 250013, China., Department of Urology, Jinan Central Hospital Affiliated to Shandong University, Jinan, Shandong Province 250013, China., Department of Urology, Jinan Central Hospital Affiliated to Shandong University, Jinan, Shandong Province 250013, China., Department of Urology, Jinan Central Hospital Affiliated to Shandong University, Jinan, Shandong Province 250013, China. Electronic address: .