Endoplasmic Reticulum Stress-Activated Cell Reprogramming in Oncogenesis

摘要

ABSTRACT Stress induced by the accumulation of unfolded proteins in the endoplasmic reticulum (ER) is observed in many human diseases, including cancers. Cellular adaptation to ER stress is mediated by the unfolded protein response (UPR), which aims at restoring ER homeo-stasis. The UPR has emerged as a major pathway in remodeling cancer gene expression, thereby either preventing cell transformation or providing an advantage to transformed cells. UPR sensors are highly regulated by the formation of dynamic protein scaffolds, leading to integrated reprogramming of the cells. Herein, we describe the regulatory mechanisms underlying UPR signaling upon cell intrinsic or extrinsic challenges, and how they engage cell transformation programs and/or provide advantages to cancer cells, leading to enhanced aggressiveness or chemoresistance. We discuss the emerging crosstalk between the UPR and related metabolic processes to ensure maintenance of protein homeostasis and its impact on cell transformation and tumor growth. Significance: ER stress signaling is dysregulated in many forms of cancer and contributes to tumor growth as a survival factor, in addition to modulating other disease-associated processes, including cell migration, cell transformation, and angiogenesis. Evidence for targeting the ER stress signaling pathway as an anticancer strategy is compelling, and novel agents that selectively inhibit the UPR have demonstrated preliminary evidence of preclinical efficacy with an acceptable safety profile. CANONICAL ER STRESS SIGNALING, ACTIVATION MECHANISMS, AND ALTERATIONS IN CANCERS Since the discovery of an adaptive response against disrupted endoplasmic reticulum (ER) homeostasis through the upregulation of specific ER-resident chaperones (1), the so-called "ER stress response" has been the subject of many studies and reviewed extensively. ER stress results from the imbalance in the folding capacity of this organelle, thus leading to the accumulation of improperly folded proteins in its lumen. To restore ER proteostasis, the cell has evolved an integrated signaling network named the unfolded protein response (UPR; ref. 2).