Abstract
The endoplasmic reticulum (ER) stress response is an adaptive mechanism that is activated upon disruption of ER homeostasis and protects the cells against certain harmful environmental stimuli. However, critical and prolonged cell stress triggers cell death. In this study, we demonstrate that Flightless-1 (FliI) regulates ER stress-induced apoptosis in colon cancer cells by modulating Ca2+ homeostasis. FliI was highly expressed in both colon cell lines and colorectal cancer mouse models. In a mouse xenograft model using CT26 mouse colorectal cancer cells, tumor formation was slowed due to elevated levels of apoptosis in FliI-knockdown (FliI-KD) cells. FliI-KD cells treated with ER stress inducers, thapsigargin (TG), and tunicamycin exhibited activation of the unfolded protein response (UPR) and induction of UPR-related gene expression, which eventually triggered apoptosis. FliI-KD increased the intracellular Ca2+ concentration, and this upregulation was caused by accelerated ER-to-cytosolic efflux of Ca2+. The increase in intracellular Ca2+ concentration was significantly blocked by dantrolene and tetracaine, inhibitors of ryanodine receptors (RyRs). Dantrolene inhibited TG-induced ER stress and decreased the rate of apoptosis in FliI-KD CT26 cells. Finally, we found that knockdown of FliI decreased the levels of sorcin and ER Ca2+ and that TG-induced ER stress was recovered by overexpression of sorcin in FliI-KD cells. Taken together, these results suggest that FliI regulates sorcin expression, which modulates Ca2+ homeostasis in the ER through RyRs. Our findings reveal a novel mechanism by which FliI influences Ca2+ homeostasis and cell survival during ER stress.
Highlights
Colorectal cancer (CRC) is one of the most common lethal cancers around the world[1]
The emergence of refractory disease following chemotherapy continues to be a major contributor to treatment failure and to the high mortality rates observed in advanced CRC
We know that the outcome of anticancer treatment can be influenced by the cancer cell response to cellular stress induced by chemotherapeutic agents
Summary
Colorectal cancer (CRC) is one of the most common lethal cancers around the world[1]. Official journal of the Korean Society for Biochemistry and Molecular Biology. Choi et al Experimental & Molecular Medicine (2020) 52:940–950 represents an emerging therapeutic target for cancer treatment[3]. The ER is a multifaceted organelle involved in initial protein maturation, lipid synthesis, and maintenance of intracellular calcium homeostasis[4]. Disruption of ER homeostasis following glucose deprivation, hypoxia, disruption of Ca2+ homeostasis, or accumulation of misfolded proteins activates the unfolded protein response (UPR) and initiates an intracellular signaling pathway that protects the cell[4]. Three ER stress sensors, protein kinase-like ER kinase (PERK), activating transcription factor 6 (ATF6), and inositolrequiring kinase-1 (IRE1), are bound to the ER-resident chaperone glucose-regulated protein-78 (GRP78/BiP)[5]
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