Flightless-1 inhibits ER stress-induced apoptosis in colorectal cancer cells by regulating Ca2+ homeostasis.
Sun Sil ChoiSang Kwon LeeJoong Kwan KimHye-Kyung ParkEujin LeeJinho JangYo Han LeeKeon Woo KhimJi-Min HyunHye-Jin EomSemin LeeByuong Heon KangYoung Chan ChaeKyungjae MyungSeung-Jae MyungChan Young ParkJang Hyun ChoiPublished in: Experimental & molecular medicine (2020)
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.
Keyphrases
- induced apoptosis
- endoplasmic reticulum stress
- cell cycle arrest
- oxidative stress
- signaling pathway
- cell death
- endoplasmic reticulum
- gene expression
- pi k akt
- diabetic rats
- poor prognosis
- computed tomography
- magnetic resonance imaging
- mouse model
- small molecule
- transcription factor
- stress induced
- risk assessment
- stem cells
- breast cancer cells
- image quality
- climate change
- dna methylation
- drug induced
- positron emission tomography
- high glucose
- endothelial cells
- heat stress
- protein protein