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

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 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 UPRrelated 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.

Overexpression of Flii during Murine Embryonic Development Increases Symmetrical Division of Epidermal Progenitor Cells

“…Consistent with our previous findings demonstrating slower development of intact skin barrier during development and post injury accompanied with slower healing in Flii Tg / Tg mice, results of this study are in agreement showing increased epidermal SCD in Flii over-expressing animals. Future studies should explore the distribution of epidermal growth factor receptor in Flii Tg/Tg mice skin and investigate if increased SCD pattern in Flii Tg / Tg mice is an adaptation to delay the onset of cancers as increased Flii levels have been suggested to promote skin, colon and breast cancer development [ 45 , 46 , 47 ].…”

Multifunctional Roles of the Actin-Binding Protein Flightless I in Inflammation, Cancer and Wound Healing

“…It is this accumulation of insoluble proteins that leads to breast cancer development in the presence of Ser436 phosphorylated Flii (He et al, 2018). High Flii levels are also found within colorectal tumor tissue, where is appears that Flii protects against endoplasmic reticulum stress induced apoptosis and results in larger tumor formation (Choi et al, 2020).…”

Omega-3 Fatty Acids DHA and EPA Reduce Bortezomib Resistance in Multiple Myeloma Cells by Promoting Glutathione Degradation

“…FLII and MAP3K19 were downregulated by fatty acids DHA/EPA. FLII has been recently reported to promote breast cancer progression via inhibiting p62-mediated selective autophagy [ 30 ] and block apoptosis in colon cancer cells by regulating Ca 2+ homeostasis [ 31 ]. MAP3K19 has been shown to activate pro-survival pathways ERK and JNK through directly phosphorylation of MEK1/2 and MKK7 [ 32 ].…”