p58IPK-Mediated Attenuation of the Proapoptotic PERK-CHOP Pathway Allows Malignant Progression upon Low Glucose

Abstract

As solid tumors expand, oxygen and nutrients become limiting owing to inadequate vascularization and diffusion. How malignant cells cope with this potentially lethal metabolic stress remains poorly understood. We found that glucose shortage associated with malignant progression triggers apoptosis through the endoplasmic reticulum (ER) unfolded protein response (UPR). ER stress is in part caused by reduced glucose flux through the hexosamine pathway. Deletion of the proapoptotic UPR effector CHOP in a mouse model of K-ras(G12V)-induced lung cancer increases tumor incidence, strongly supporting the notion that ER stress serves as a barrier to malignancy. Overcoming this barrier requires the selective attenuation of the PERK-CHOP arm of the UPR by the molecular chaperone p58(IPK). Furthermore, p58(IPK)-mediated adaptive response enables cells to benefit from the protective features of chronic UPR. Altogether, these results show that ER stress activation and p58(IPK) expression control the fate of malignant cells facing glucose shortage.

Inhibition of HSP90 by AUY922 Preferentially Kills Mutant KRAS Colon Cancer Cells by Activating Bim through ER Stress

“…It seems therefore that other agents that induce ER stress may cooperate with HSP90 inhibition to induce apoptosis in mutant KRAS colon cancer cells. In support with our findings in mutant KRAS colon cancer, deletion of CHOP in a mouse model of mutant KRAS-induced lung cancer increases tumor incidence, suggesting that CHOP activity is a barrier to mutant KRAS-driven malignancy (42).…”

Endoplasmic reticulum proteostasis in glioblastoma—From molecular mechanisms to therapeutic perspectives

“…Drugs inducing further ER stress (such as salinomycin) sensitize glioma cells to TMZ treatment through the down-regulation of MGMT, N-methylpurine DNA glycosylase (MPG), and RAD51, three gene products involved in DNA repair (217), indicating that TMZ-mediated toxicity through the DNA damage pathway may interfere with the ER stress response, although the precise underlying molecular mechanisms remain unclear. Another approach would be to classify cancer cells as showing a selective advantage on the basis of high basal ER stress signaling activity, as previously shown in the case of oncogene-induced cell transformation (218). In this context, tumor cells exhibiting high basal ER stress signaling activity could represent good targets for drugs that selectively impair UPR adaptive signaling (as described in Table 1), and hence, resistance to treatments (most likely caused by either high adaptive capacity or hormesis-adaption through low-dose exposure) (219) observed in the cancer cells could be dampened through selective inhibition of the three arms of the UPR.…”

Physiological/pathological ramifications of transcription factors in the unfolded protein response

“…The incidence of K-ras (G12V)-induced lung cancer is markedly enhanced in the absence of CHOP (Huber et al 2013), suggesting an anticancer activity of CHOP. As a well-known proapoptotic gene, CHOP is considered a drug target for cancer (Schonthal 2013).…”