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Review
. 2019 Mar 7:12:1857-1865.
doi: 10.2147/OTT.S194770. eCollection 2019.

Targeting off-target effects: endoplasmic reticulum stress and autophagy as effective strategies to enhance temozolomide treatment

Yichun He  1 , Jing Su  2 , Beiwu Lan  1 , Yufei Gao  1 , Jingxia Zhao  3
Affiliations
Review

Targeting off-target effects: endoplasmic reticulum stress and autophagy as effective strategies to enhance temozolomide treatment

Yichun He et al. Onco Targets Ther. .

Abstract

Glioblastoma multiforme (GBM) is the most common and aggressive adult primary central nervous system tumor. Unfortunately, GBM is resistant to the classic chemotherapy drug, temozolomide (TMZ). As well as its classic DNA-targeting effects, the off-target effects of TMZ can have pro-survival or pro-death roles and regulate GBM chemoradiation sensitivity. Endoplasmic reticulum (ER) stress is one of the most common off-target effects. ER stress and its downstream induction of autophagy, apoptosis, and other events have important roles in regulating TMZ sensitivity. Autophagy is an evolutionarily conserved cellular homeostasis mechanism that is closely associated with ER stress-induced apoptosis. Under ER stress, autophagy cannot only remove misfolded/unfolded proteins and damaged organelles and degrade and inhibit apoptosis-related caspase activation to reduce cell damage, but may also promote apoptosis dependent on ER stress intensity. Although some protein interactions between autophagy and apoptosis and common upstream signaling pathways have been found, the underlying regulatory mechanisms are still not fully understood. This review summarizes the possible mechanisms underlying the current known off-target roles of ER stress and downstream autophagy in the regulation of cell fate and evaluates their role in TMZ treatment and their potential as therapeutic targets.

Keywords: apoptosis; autophagy; chemotherapy resistance; endoplasmic reticulum stress; glioma; temozolomide.

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Conflict of interest statement

Disclosure The authors report no conflicts of interest in this work.

Figures

Figure 1
Figure 1
Schematic representation of the functional relationship between unfolded protein response, autophagy, apoptosis, and glioma cell fate under TMZ treatment. Notes: Under TMZ treatment, ER stress (unfolded protein response), autophagy, and apoptosis occur in glioma cells. Complex interactions between these pathways determine the fate of glioma cells. The UPR regulates autophagy through the PERK, XBP1, and other pathways, and autophagy can degrade misfolded protein aggregates or damaged organelles through a lysosome-associated degradation system. Meanwhile, upon ER stress stimulation, the UPR can facilitate apoptosis via CHOP, JNK, ATF6, and other pathways, or inhibit apoptosis through global translational control, and by regulating folding capacity and misfolded protein degradation through a proteasome-associated degradation system. iDISC formation and XIAP degradation are critical in the process of autophagy upregulation of apoptosis. However, autophagy can also inhibit apoptosis through nutrient recycling and elimination of damaged organelles. Abbreviations: ER, endoplasmic reticulum; TMZ, temozolomide; UPR, unfolded protein response.
Figure 2
Figure 2
Common upstream signaling pathways of autophagy and apoptosis under ER stress and the mechanisms of autophagy involved in determining cell fate under different intensities of ER stress. Notes: Under ER stress, the unfolded protein response is activated, resulting in activation of PERK and phosphorylation of eIF2α. Selective induction of ATF4 occurs, which can promote the transcription of genes involved in autophagy, apoptosis, molecule chaperoning, ER-associated degradation, and metabolism. Moreover, ATF4 can also activate apoptosis via degradation of XIAP and cooperation with CHOP under prolonged ER stress. IRE1 activates XBP1, ASK1, and molecules downstream of JNK that promote autophagy and apoptosis. Through XBP1 and CHOP, ATF6 can indirectly regulate autophagy or apoptosis. Thus, the effects of ER stress-induced autophagy on cell survival have dual roles including pro-survival and pro-death. On one hand, autophagy can inhibit apoptosis through clearing misfolded/unfolded proteins and damaged organelles and inhibiting or degrading caspases, resulting in protecting cells from damages induced by ER stress. On the other hand, autophagy can serve as a platform for caspase-8 activation and degrade IAPs, which amplifies cell injury induced by ER stress. Abbreviations: ER, endoplasmic reticulum; TMZ, temozolomide.
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