ERK1/2 signalling protects against apoptosis following endoplasmic reticulum stress but cannot provide long-term protection against BAX/BAK-independent cell death

Abstract

Disruption of protein folding in the endoplasmic reticulum (ER) causes ER stress. Activation of the unfolded protein response (UPR) acts to restore protein homeostasis or, if ER stress is severe or persistent, drive apoptosis, which is thought to proceed through the cell intrinsic, mitochondrial pathway. Indeed, cells that lack the key executioner proteins BAX and BAK are protected from ER stress-induced apoptosis. Here we show that chronic ER stress causes the progressive inhibition of the extracellular signal-regulated kinase (ERK1/2) signalling pathway. This is causally related to ER stress since reactivation of ERK1/2 can protect cells from ER stress-induced apoptosis whilst ERK1/2 pathway inhibition sensitises cells to ER stress. Furthermore, cancer cell lines harbouring constitutively active BRAFV600E are addicted to ERK1/2 signalling for protection against ER stress-induced cell death. ERK1/2 signalling normally represses the pro-death proteins BIM, BMF and PUMA and it has been proposed that ER stress induces BIM-dependent cell death. We found no evidence that ER stress increased the expression of these proteins; furthermore, BIM was not required for ER stress-induced death. Rather, ER stress caused the PERK-dependent inhibition of cap-dependent mRNA translation and the progressive loss of pro-survival proteins including BCL2, BCLXL and MCL1. Despite these observations, neither ERK1/2 activation nor loss of BAX/BAK could confer long-term clonogenic survival to cells exposed to ER stress. Thus, ER stress induces cell death by at least two biochemically and genetically distinct pathways: a classical BAX/BAK-dependent apoptotic response that can be inhibited by ERK1/2 signalling and an alternative ERK1/2- and BAX/BAK-independent cell death pathway.

Splice switching an oncogenic ratio of SmgGDS isoforms as a strategy to diminish malignancy

“…Reduced ERK activity caused by SSO Ex5 may also promote ER stress and the UPR. The small GTPases RhoA, Rac1, and NRas are reported to protect cells from ER stress and the UPR by activating ERK (62)(63)(64)(65)(66)(67), and activation of ERK promotes cell survival following ER stress (68). Since SSO Ex5 suppresses the prenylation of these small GTPases, the resulting decrease in their downstream signaling may diminish ERK activity and induce ER stress and the UPR.…”

Exercise training protects human and rodent β cells against endoplasmic reticulum stress and apoptosis

“…protection against H 2 O 2 (44). Furthermore, ERK1/2 activation protects fibroblasts against cell death induced by the ER stressor tunicamycin (45). The antiapoptotic protein Bcl2-A1 plays an important role in the protection of b cells against cytokine-or CPA-induced apoptosis by counteracting Bcl-2 homology-3-only proapoptotic proteins (46).…”

Proteotoxic Stress and Cell Death in Cancer Cells

“…Certainly, the augmented levels of ROS and calcium can be responsible for the induction of alternative forms of death in response to the proteotoxic stress observed in different studies [153,154]. In general, the appearance of nonapoptotic or alternative forms of cell death in response to proteotoxic stress is a less investigated item [155][156][157]. Frequently, these necrotic-like responses appear when apoptosis is defective.…”