Role of mapks in er stress-related cell cycle arrest and apoptosis

Official URL: http://192.168.1.20/record=b1228187 (Table of Contents)

Endoplasmic reticulum (ER) stress has been implicated in many diseases and cancer therapy. The unfolded protein response (UPR) is activated in the face of ER stress to alleviate it. The survival elements pertaining to the UPR are being investigated for a more effective deathinduction in cancer cells that have adapted to chronic ER stress and display resistance to treatment. Mitogen-activated protein kinase (MAPK) JNK is implicated in cell proliferation, survival and death. JNK is activated during the UPR . We report in this study that the inhibition of the JNK pathway has different outcomes; depending on the phase of the ER stress response in HCT116 colon carcinoma cells treated with the asparagine-linked glycosylation inhibitor tunicamycin (TM). Both outcomes indicate a cytoprotective role for JNK activity during ER stress -related cell survival and death. TM treatment at 1 μg/ml induced cell cycle arrest at the G1 phase. Cell cycle arrest can be interpreted as a cytoprotective response that conserves energy as an adaptation strategy to ER stress. Inhibition of JNK by the small molecule SP600125 led cells bypass this arrest compared to TM-treated HCT116 cells. Cell proliferation in response to JNK -inhibition was observed by light microscopy. Accordingly, p21CİP1 protein, a cyclin-dependent kinase inhibitor (CKI) that causes cell cycle arrest at the G1 to S transition was elevated in TM - treated cells, whereas JNK inhibition abrogated this upregulation. It has been reported that JNK activity stabilizes p21CİP1, which has short half-life of 20 – 60 min. TM-induced apoptosis involved cas pase-3 and -8 activation and cells were partially rescued from death by the administration of the pan -caspase inhibitor z-VAD-fmk. Initiation of apoptosis coincided with the increase in p21CİP1 levels in JNK-inhibited TM-treated cells after 24 h of treatment. JNK inhibition caused a 2 -fold increase in apoptosis in TM -treated cells after 24 h, after which the effect of JNK inhibition did not increase cell death. Inhibition of the MAPKs p38 and ERK did not effect the cell cycle distribution of TM -treated cells and there was no change in the apoptotic response after 24 h of treatment. p38 and ERK inhibition sensitized HCT116 cells to ER stress -related apoptosis after 40 h of treatment. In thi s experimental model, JNK and p38 and ERK differed temporally in their prosurvival roles, presumably due to the condition of the cell and the availability of affected substrates.