Linking ER Stress to Autophagy: Potential Implications for Cancer Therapy

Abstract

Different physiological and pathological conditions can perturb protein folding in the endoplasmic reticulum, leading to a condition known as ER stress. ER stress activates a complex intracellular signal transduction pathway, called unfolded protein response (UPR). The UPR is tailored essentially to reestablish ER homeostasis also through adaptive mechanisms involving the stimulation of autophagy. However, when persistent, ER stress can switch the cytoprotective functions of UPR and autophagy into cell death promoting mechanisms. Recently, a variety of anticancer therapies have been linked to the induction of ER stress in cancer cells, suggesting that strategies devised to stimulate its prodeath function or block its prosurvival function, could be envisaged to improve their tumoricidial action. A better understanding of the molecular mechanisms that determine the final outcome of UPR and autophagy activation by chemotherapeutic agents, will offer new opportunities to improve existing cancer therapies as well as unravel novel targets for cancer treatment.

Figure 1

The unfolded protein response in adaptive, apoptotic and redox responses. Upon accumulation of misfolded proteins in the ER, the release of BiP allows IRE1 and PERK to oligomerize. Oligomerized IRE1 disposes of an intrinsic endoribonuclease activity that mediates the unconventional splicing of XBP1mRNA which is subsequently translated into XBP1s, a potent transcription factor regulating expression of genes involved in ERAD and ER quality control. IRE1 signaling is positively regulated by binding of the multidomain proapoptotics Bax and Bak, while its activity is suppressed by the transmembrane protein BI-1. The interaction of Bax/Bak with IRE1 is required for the recruitment of TRAF2 and ASK1 leading to the activation of the MAPKs JNK and p38 MAPK, through specific MKKs. Oligomerized PERK phosphorylates the translation initiating factor eIF2α, resulting in suppression of general protein translation while favoring the translation ATF4, which induces the expression of genes involved in restoring ER homeostasis. Phosphorylation of Nrf2 by PERK disrupts its association with Keap1 resulting in its nuclear accumulation and upregulation of genes associated with various antioxidant responses. In contrast to PERK and IRE1, release of BiP from ATF6 induces its translocation to the Golgi where its processing generates an active transcription factor. Cleaved ATF6 controls mainly genes involved in ERAD and ER homeostasis. Upon severe ER stress, ATF4, XBP1s, and ATF6 can upregulate the expression of the proapoptotic transcription factor CHOP, which mediates apoptosis by the upregulation of proapoptotic BH3-only protein Bim and by suppressing Bcl-2 expression. CHOP activity is enhanced through phosphorylation by p38MAPK. Phosphorylation by JNK in turn activates Bim while inhibiting Bcl-2 functions.

Figure 2

Mechanisms connecting ER stress and autophagy. Different ER stresses lead to autophagy activation. Ca²⁺ release from the ER can stimulate different kinases that regulate autophagy. CaCMKKβ phosphorylates and activates AMPK which leads to mTORC1 inhibition; DAPK phosphorylates Beclin-1 promoting its dissociation from Bcl-2; PKCθ activation may also promote autophagy independently of mTORC1. Inositol 1,4,5-trisphosphate receptor (IP3R) interacts with Beclin-1. Pharmacological inhibition of IP3R may lead to autophagy in a Ca²⁺-independent manner by stimulating its dissociation from Beclin-1. The IRE1 arm of ER stress leads to JNK activation and increased phosphorylation of Bcl-2 which promotes its dissociation from Beclin-1. Increased phosphorylation of eIF2α in response to different ER stress stimuli can lead to autophagy through ATF4-dependent increased expression of Atg12. Alternatively, ATF4 and the stress-regulated protein p8 promote the up-regulation of the pseudokinase TRB3 which leads to inhibition of the Akt/mTORC1 axis to stimulate autophagy.

Figure 3

Hypothetic therapeutic strategies based on the modulation of ER stress and autophagy. Different strategies involving modulation of ER stress and autophagy could be potentially used in antitumoral therapies. A. One type of antitumoral agents (e.g., cannabinoids) activates ER stress and autophagy as a mechanism to promote cancer cell death. In these cases, strategies aimed at increasing the stimulation of ER stress and autophagy might be beneficial; B. Other anticancer agents (e.g., PDT) activate ER stress as part of the mechanisms by which they promote cancer cell death. Secondary ER stress-induced activation of autophagy may contribute to cell death (in apoptosis-deficient cells) or to cell survival (in apoptosis competent cells). Thus, depending on the tumor features, autophagy inhibitors or inducers might be administered to improve the response to these anticancer agents. C. A third type of antitumoral agents (e.g., Imatinib mesilate) activates a protective ER stress/autophagy response secondarily to its primary antitumoral mechanism. Inhibition of ER stress and/or autophagy would help to reduce the resistance to this type of therapy.