Critical Role of Endogenous Akt/IAPs and MEK1/ERK Pathways in Counteracting Endoplasmic Reticulum Stress-induced Cell Death

Abstract

Endoplasmic reticulum (ER) stress has been implicated in the pathogenesis of many diseases and in cancer therapy. Although the unfolded protein response is known to alleviate ER stress by reducing the accumulation of misfolded proteins, the exact survival elements and their downstream signaling pathways that directly counteract ER stress-stimulated apoptotic signaling remain elusive. Here, we have shown that endogenous Akt and ERK are rapidly activated and act as downstream effectors of phosphatidylinositol 3-kinase in thapsigargin- or tunicamycin-induced ER stress. Introduction of either dominant-negative Akt or MEK1 or the inhibitors LY294002 and U0126 sensitized cells to ER stress-induced cell death in different cell types. Reverse transcription-PCR analysis of gene expression during ER stress revealed that cIAP-2 and XIAP, members of the IAP family of potent caspase suppressors, were strongly induced. Transcription of cIAP-2 and XIAP was up-regulated by the phosphatidylinositol 3-kinase/Akt pathway as shown by its reversal by dominant-negative Akt or LY294002. Ablation of these IAPs by RNA interference sensitized cells to ER stress-induced death, which was reversed by the caspase inhibitor benzyloxycarbonyl-VAD-fluoromethyl ketone. The protective role of IAPs in ER stress coincided with Smac release from mitochondria to the cytosol. Furthermore, it was shown that mTOR was not required for Akt-mediated survival. These results represent the first demonstration that activation of endogenous Akt/IAPs and MEK/ERK plays a critical role in controlling cell survival by resisting ER stress-induced cell death signaling.

Activating transcription factor 6 protects insulin receptor from ER stress-stimulated desensitization via p42/44 ERK pathway

“…As previously published [43,46] , short-term (from 0 to 4 h) ER stress stimulation could increase AKT activity, while long-term (from 8 to 12 h) stimulation could suppress AKT activity. This reflects the dual character of ER stress: the adaptive/moderate level stress (featured by increased chaperone proteins and decreased misfolded proteins) and the destructive/excessive level stress (featured by activating JNK, apoptosis signal-regulating kinase (ASK)) [2,3,30,47] .…”

“…Several diabetes-inducing agents have also been demonstrated as causing insulin resistance in a MEK-dependent manner [35,20] . ER stress was also reported to induce activation of ERK [46] , and ATF6 was shown to counteract the effects of ER stress [23,24] . Based on this prior evidence and our results (Figures 4 and 5), it could be concluded that excessive ER stress could increase the basal, but decrease the insulin-induced, activity of ERK.…”

Inhibition of Akt Potentiates 2-DG–Induced Apoptosis via Downregulation of UPR in Acute Lymphoblastic Leukemia

“…Phosphorylation/activation of Akt results in upregulation of the glucose transporter GLUT1 and promotes the translocation of hexokinase into the mitochondria (45). It has also been reported that in addition to UPR, ER stress activates parallel endogenous cell survival mechanisms that directly buffer apoptotic signals through the Akt and ERK pathways (29) and via the antiapoptotic proteins cIAP-2 and XIAP (46). We show that the inhibition of Akt in 2-DGtreated ALL cells results in synergistic cell death.…”

Participation of endoplasmic reticulum stress in the pathogenesis of spontaneous glomerulosclerosis–Role of intra-renal angiotensin system

“…In addition to PERK, phosphorylated Akt can activate Nrf2 and thereby participate in the ER stress-associated prosurvival response. 34 Prolonged ER stress has been shown to suppress phosphorylation of Akt and thereby promote apoptosis. 35 Consistent with these findings, phosphorylated Akt abundance was markedly reduced in the kidneys of our untreated Imai rats.…”