Study summary · research use only
AICAR induces AMPK-independent programmed necrosis in prostate cancer cells
Plain-language summary
Paraphrased from the published abstract below — not a verdict on whether anything works.
This in vitro study examined AICAR (5-Aminoimidazole-4-carboxamide riboside, also called acadesine), an AMP-activated protein kinase (AMPK) agonist, in three human prostate cancer cell lines (LNCaP, PC-3, and PC-82). AICAR was reported to primarily induce programmed necrosis rather than apoptosis in these cells, and this effect was reported to be largely reduced by the necrosis inhibitor necrostatin-1. The mitochondrial protein cyclophilin-D (CYPD) was reported to be required for this AICAR-induced necrosis, as CYPD inhibitors (cyclosporin A and sanglifehrin A) and CYPD shRNAs markedly reduced AICAR-induced necrosis and cytotoxicity. The necrosis was reported to occur independently of AMPK but to require reactive oxygen species (ROS), since ROS scavengers (N-acetylcysteine and MnTBAP), but not AMPKα shRNAs, largely inhibited the necrosis and cytotoxicity caused by AICAR.
Abstract
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.
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