ER-phagy in the Occurrence and Development of Cancer

Abstract

As an organelle, the endoplasmic reticulum (ER) is closely related to protein synthesis and modification. When physiological or pathological stimuli induce disorders of ER function, misfolded proteins trigger ER-phagy, which is beneficial for restoring cell homeostasis or promoting cell apoptosis. As a double-edged sword, ER-phagy actively participates in various stages of development and progression in tumor cells, regulating tumorigenesis and maintaining tumor cell homeostasis. Through the unfolded protein response (UPR), the B cell lymphoma 2 (BCL-2) protein family, the Caspase signaling pathway, and others, ER-phagy plays an initiating role in tumor occurrence, migration, stemness, and proliferation. At the same time, many vital proteins strongly associated with ER-phagy, such as family with sequence similarity 134 member B (FAM134B), translocation protein SEC62 (SEC62), and C/EBP-homologous protein (CHOP), can produce a marked effect in many complex environments, which ultimately lead to entirely different tumor fates. Our article comprehensively focused on introducing the relationship and interaction between ER-phagy and cancers, as well as their molecular mechanism and regulatory pathways. Via these analyses, we tried to clarify the possibility of ER-phagy as a potential target for cancer therapy and provide ideas for further research.

Keywords: ER-phagy; apoptosis; cancer; unfolded protein response.

Figure 1

The essential receptors of ER-phagy. Generally, FAM134B, SEC62, and CCPG1 are located in the ER sheets, while RTN3, ATL3, and TEX264 exist in the tubular ER; meanwhile, p62, CALCOCO1, and C53 are three soluble receptors that are distributed in different regions. Although they have various functional motifs and locations, they all play indispensable roles in ER-phagy and have unique interactions with the development of cancer. For instance, FAM134B and RTN3 are activated upon amino acid deprivation, while SEC62 and CCPG1 play more roles in ER-phagy induced by drugs. In its relationship with tumors, FAM134B can inhibit tumor cell migration, while SEC62 can promote the invasion and metastasis ability of cancer cells. The other functions of these receptors in ER-phagy and cancer require further research.

Figure 2

Molecular mechanism of the unfolded protein response and ER-phagy. Under normal physiological conditions, GRP78 can inhibit the activity of IRE1, ATF6, and PERK. Under ER stress, the misfolded proteins can lead to their dissociation from GRP78 and trigger downstream signal propagation. IRE1 interacts with TRAF2 and generates XBP1s, then prompts ER-phagy through the JNK and p38MAPK pathways. ATF6 is transported to the Golgi apparatus and is cleaved to form XBP1s, thus regulating CHOP and its downstream targets, such as the BCL-2 protein family and Caspase signal transduction, resulting in the aggravation of ER-phagy and cell apoptosis. PERK can phosphorylate eIF2α to inhibit protein synthesis, while ATF4 containing short open reading frames is increased and facilitates CHOP, AMPK, Sestrin-2, and DDIT4 to regulate ER-phagy and apoptosis.