Flightless-1 inhibits ER stress-induced apoptosis in colorectal cancer cells by regulating Ca2+ homeostasis

• Published in: Experimental & molecular medicine Vol. 52; no. 6; pp. 940 - 950
• Main Authors: Choi, Sun Sil, Lee, Sang Kwon, Kim, Joong Kwan, Park, Hye-Kyung, Lee, Eujin, Jang, Jinho, Lee, Yo Han, Khim, Keon Woo, Hyun, Ji-Min, Eom, Hye-jin, Lee, Semin, Kang, Byuong Heon, Chae, Young Chan, Myung, Kyungjae, Myung, Seung-Jae, Park, Chan Young, Choi, Jang Hyun
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.06.2020; Springer Nature B.V; Nature Publishing Group; 생화학분자생물학회
• Subjects: 14/34; 631/67; 631/80/82/23; 64/60; 82/80; 96/2; 96/31; Animal models; Apoptosis; Biomedical and Life Sciences; Biomedicine; Calcium (intracellular); Calcium (reticular); Calcium efflux; Calcium homeostasis; Calcium signalling; Cell death; Cell survival; Chemotherapy; Colon cancer; Colorectal cancer; Colorectal carcinoma; Cytoskeleton; Endoplasmic reticulum; Environmental effects; Filaments; Gene expression; Homeostasis; Intracellular; Medical Biochemistry; Molecular Medicine; Protein folding; Proteins; Ryanodine receptors; Stem Cells; Stress; Therapeutic targets; Tumor cell lines; Tumor cells; Tumors; Xenografts; 생화학
• ISSN: 1226-3613; 2092-6413; 2092-6413
• DOI: 10.1038/s12276-020-0448-3

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 Ca 2+ 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 Ca 2+ concentration, and this upregulation was caused by accelerated ER-to-cytosolic efflux of Ca 2+ . The increase in intracellular Ca 2+ 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 Ca 2+ 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 Ca 2+ homeostasis in the ER through RyRs. Our findings reveal a novel mechanism by which FliI influences Ca 2+ homeostasis and cell survival during ER stress. Cancer: Protein enhances survival of tumor cells under stress A cytoskeletal protein that helps tumors avoid cell death offers a promising new drug target for fighting cancer. A team led by Jang Hyun Choi and Sun Sil Choi of the Ulsan National Institute of Science and Technology, South Korea, detailed how a protein called Flightless I (FliI) that normally regulates the remodeling of structural filaments in the cell can, in colorectal cancer cells, serve as a tumor promoter through its action on calcium levels. Typically, cells respond to chronic stress by altering calcium signaling to promote their own death. In tumors, however, FliI maintains normal calcium levels to enhance cell survival even in the face of chemotherapy and other stressful stimuli. Suppressing FliI activity could thus help sensitize cancer cells to other stress- and death-inducing drug regimens.