Endoplasmic Reticulum Stress and the Hallmarks of Cancer

Abstract

Tumor cells are often exposed to intrinsic and external factors that alter protein homeostasis, thus producing endoplasmic reticulum (ER) stress. To cope with this, cells evoke an adaptive mechanism to restore ER proteostasis known as the unfolded protein response (UPR). The three main UPR signaling branches initiated by IRE1α, PERK, and ATF6 are crucial for tumor growth and aggressiveness as well as for microenvironment remodeling or resistance to treatment. We provide a comprehensive overview of the contribution of the UPR to cancer biology and the acquisition of malignant characteristics, thus highlighting novel aspects including inflammation, invasion and metastasis, genome instability, resistance to chemo/radiotherapy, and angiogenesis. The therapeutic potential of targeting ER stress signaling in cancer is also discussed.

IRE1α RNase–dependent lipid homeostasis promotes survival in Myc-transformed cancers

“…If these responses do not restore ER homeostasis, persistent UPR signaling can ultimately trigger apoptosis (9). The UPR has recently been appreciated as a central player in tumor development, making it an appealing target in both solid and hematological malignancies (45,46). However, several fundamental issues need to be addressed to rationally target the UPR and improve patient outcomes.…”

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

“…The concept of ER proteostasis addiction has been proposed as a mechanism supporting tumor growth and malignant cell transformation (33). It is now widely acknowledged that cancer cells may exploit the prosurvival signals of the UPR to cope with both intrinsic and extrinsic stresses and escape apoptosis as well as modulate other disease-associated processes including migration, invasion, angiogenesis, and inflammation [reviewed in (33,34)]. Overall, accumulating evidence indicates that UPR signaling modulates almost all hallmarks of cancer (34).…”

GRP78 haploinsufficiency suppresses acinar-to-ductal metaplasia, signaling, and mutant Kras -driven pancreatic tumorigenesis in mice

“…A characteristic of pancreatic cancer is the formation of a dense stroma termed "desmoplastic reaction" that induces vascular collapse leading to severe hypoxia and glucose deprivation (1). As an adaptive measure, cancer cells turn on the unfolded protein response (UPR) (10,11,13). ER stress induction of GRP78 in Significance KRAS is mutated in more than 90% of pancreatic adenocarcinoma (PDAC).…”

“…Cancer cells are subjected to ER stress due to intrinsic factors such as genetic mutations, altered metabolism, and hyperproliferation as well as extrinsic factors in the tumor microenvironment including oxygen and nutrient deprivation (10)(11)(12)(13). A characteristic of pancreatic cancer is the formation of a dense stroma termed "desmoplastic reaction" that induces vascular collapse leading to severe hypoxia and glucose deprivation (1).…”