AKT is indispensable for coordinating Par-4/JNK cross talk in p21 downmodulation during ER stress

Abstract

The double-edged role of p21 to command survival and apoptosis is emerging. The current investigation highlights ER stress-mediated JNK activation that plausibly triggers cell death by attenuating endogenous p21 level. Here, we demonstrated that ER stress activator 3-AWA diminishes the p21 levels in cancer cells by averting the senescent phenotype to commence G2/M arrest. In essence, the deceleration in p21 level occurs through ER stress/JNK/Caspase-3 axis via activation/induction of proapoptotic Par-4 and inhibition of AKT. The molecular dynamics studies identified important interactions, which may be responsible for the AKT inhibition and efficacy of 3-AWA towards AKT binding pocket. Interestingly, the p21 deceleration was rescued by incubating the cells with 3-AWA in the presence of an ER stress inhibitor, Salubrinal. Furthermore, we demonstrated that p21 expression decreases solitarily in Par-4+/+ MEFs; albeit, ER stress-induced JNK activation was observed in both Par-4+/+ and Par-4−/− MEFs. Par-4 knockdown or overexpression studies established that ectopic Par-4 along with ER stress are not sufficient to downregulate p21 in PC-3 cells but are adequate for DU-145 cells and that the ER stress inflicted activation of JNK, inhibition of AKT and Par-4 induction are all crucial to p21 downmodulation by 3-AWA. By using isogenic cell lines, such as HCT-116 p53+/+ and HCT-116 p53−/−, we found that deceleration in p21 expression due to ER stress is p53 independent. Moreover, in orthotopic carcinogen-induced rat colorectal carcinoma model, we found that 3-AWA inhibits colorectal tumor growth and formation of colorectal polyps at a tolerable dose, similar to the first-line drug for colorectal cancer-5-fluorouracil.

125 I seeds irradiation inhibits tumor growth and induces apoptosis by Ki-67, P21, Survivin，Livin and Caspase-9 expression in lung carcinoma xenografts

“…Moreover, p21 shields the cancer cells from death induced by DNA-damaging agents, and altered p21 expression increases sensitivity to treatment in vivo (47,49). P21 is an apoptosis regulatory factor, which is due to inhibition of the activity of procaspase-3 (48) In conclusion, our study successfully establishes the mouse lung adenocarcinoma model and provides a beneficial exploration of radiobiology of continuous different dose 125I seed irradiation in the treatment of lung adenocarcinoma.…”

“…P21 is one of the most important negative regulatory factors in the cell cycle and also plays a very important role in the process of apoptosis and cell proliferation (47)(48)(49). P21 mainly regulate the activity of intracellular CDK (cyclin dependent kinase) leaving the cells in the G1 or G2 phase (47)(48)(49), through the regulation of tumor suppressor gene p53, but also by p53-dependent manner by other factors induced by the production. Ki67 have been described as a reliable indicator in the rate of cell proliferation, which is a proliferation marker expression in cells expression throughout all stages except G0 phase (45).…”

“…The central event in apoptosis is the proteolytic activation of a class of cysteine aspartyl-specific proteases(Caspase) family (38,45,(50)(51)(52)(53)(54)(55). Caspases are known to act as important mediators of apoptosis and contribute to the overall apoptotic morphology by the cleavage of various cellular substrates (44,49,54). Caspase-3 is an important regulator of apoptosis and key enzyme in the Caspase family, and most factors initiate apoptosis through caspase − 3-mediated pathway (37,44).…”

“…The increase of caspase-3 expression may induce the mitochondria-dependent apoptotic pathway with the possible mitochondria-independent pathway for the caspase-8 activation for that caspase-8-mediated apoptosis induced by oxidative stress is independent of the intrinsic pathway and dependent on cathepsins (38,45,(50)(51)(52)(53)(54)(55). The intrinsic pathway of apoptosis is associated with the activation of caspase-9, which cleaves and activates caspase-3 (49)(50)(51)(52)(53)(54).…”

125 I seeds irradiation inhibits tumor growth and induces apoptosis by Ki-67, P21, Survivin，Livin and Caspase-9 expression in lung carcinoma xenografts

“…(41,49). P21 is one of the most important negative regulatory factors in the cell cycle and also plays a very important role in the process of apoptosis and cell proliferation (50)(51)(52). P21 mainly regulate the activity of intracellular CDK (cyclin dependent kinase) leaving the cells in the G1 or G2 phase(50-52) , through the regulation of tumor suppressor gene p53, but also by p53-dependent manner by other factors induced by the production.…”