Abstract
As the first compartment of the protein secretory pathway, the endoplasmic reticulum (ER) acts as a protein synthesis factory, maintaining proteostasis and ER homeostasis. However, a variety of intrinsic and extrinsic perturbations, such as cancer, can disrupt the homeostasis and result in a large accumulation of misfolded/unfolded proteins in the ER lumen, thereby provoking a specific cellular state addressed as “ER stress”. Then the unfolded protein response (UPR), an adaptive signaling pathway, is triggered to address the stress and restore the homeostasis. A novel aspect of ER stress is that it can be transmitted from cancer cells to tumor-infiltrating myeloid cells through certain cancer cell-released soluble factors, which is termed as transmissible ER stress (TERS) or ER stress resonance (ERSR). In this review, we provide a comprehensive overview of the link between cancer and ER stress as well as the possible soluble factors mediating TERS. We further elaborate the cell-extrinsic effects of TERS on tumor immunity, and how it indirectly modulates cancer development and progression, which is expected to add a new dimension to anticancer therapy.
Highlights
The endoplasmic reticulum (ER) is an intracellular membranous organelle
As an adaptive signaling pathway, the unfolded protein response (UPR) is Transmissible Endoplasmic Reticulum Stress predominantly controlled by three transmembrane ER stress sensors: activating transcription factor 6 (ATF6), inositolrequiring enzyme 1 (IRE1) and protein kinase RNA-like ER kinase (PERK) (Zheng et al, 2016)
If the UPR fails to get rid of the stress, the UPR signals may switch from pro-survival to prodeath, including apoptosis, necroptosis and autophagic cell death (Sano and Reed, 2013; Hetz and Papa, 2018; Kim and Kim, 2018; Almanza et al, 2019)
Summary
As the first compartment of the protein secretory pathway, the ER acts as a protein synthesis factory It is involved in the production, folding, modification, maturation, quality control and degradation of approximately one-third of all cellular proteins, and makes certain that only properly folded proteins can be transported to their intracellular or extracellular sites of action (Braakman and Bulleid, 2011; Stefan et al, 2011). Active ATF6 will translocate to the Golgi apparatus, while active IRE1 and PERK will subsequently activate downstream signaling cascades, driving mutually reinforcing signaling pathways for a common purpose: to initiate corrective measures to reestablish protein homeostasis and promote cell survival (Ye et al, 2000; Shen et al, 2002; Hetz, 2012; Sano and Reed, 2013; Frakes and Dillin, 2017). If the UPR fails to get rid of the stress, the UPR signals may switch from pro-survival to prodeath, including apoptosis, necroptosis and autophagic cell death (Sano and Reed, 2013; Hetz and Papa, 2018; Kim and Kim, 2018; Almanza et al, 2019)
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