Calmodulin/CaMKII-γ mediates prosurvival capability in apicidin-persistent hepatocellular carcinoma cells via ERK1/2/CREB/c-fos signaling pathway.

Calmodulin (CaM), a Ca2+ binding protein, plays a critical role in cancer initiation and progression through binding and activating numerous target proteins, including Ca2+ /calmodulin-dependent protein kinase (CaMK) family proteins. However, the mechanisms underlying the effects of CaM/CaMKs on the survival capability of liver cancer cells is unclear, and this study investigates this mechanism in apicidin-persistent HA22T cells. CaM level was upregulated, especially in the cytosol, in apicidin-persistent HA22T cells than in parental HA22T cells and was positively associated with cell proliferation and migration capacity of apicidin-persistent HA22T cells. Further, the expression of CaM-activated CaMKs-dependent signaling cascades, including CaMKK2, CaMKIV, CaMKII-γ, and p-CaMKII was observed in apicidin-persistent HA22T cells, which were transiently activated by mitogen-activated protein kinase oncogenic signaling, such as CREB, ERK1/2, and c-fos. Furthermore, a specific CaM inhibitor trifluoperazine reduced the levels of p-CREB, p-ERK1/2, and c-fos in apicidin-persistent HA22T cells than in parental HA22T cells. Additionally, inhibition of CaM also suppressed CaM-induced Bcl-XL (an antiapoptotic protein) expression in apicidin-persistent HA22T cells. Our finding emphasizes an essential role of CaM/CaMKs in augmentation of the survival capability of apicidin-persistent liver cancer cells and suggests that CaM inhibition significantly attenuates CaM-induced tumor growth and abrogates antiapoptotic function and also offers a promising therapeutic target for cancer treatment. © 2021 Wiley Periodicals LLC.

Citation

Wei-Chung Hsu, Hang-Nga Le, Yu-Jung Lin, Ming-Cheng Chen, Tso-Fu Wang, Chi-Cheng Li, Wei-Wen Kuo, B Mahalakshmi, Chaouhan Hitesh Singh, Mei-Chih Chen, Chih-Yang Huang. Calmodulin/CaMKII-γ mediates prosurvival capability in apicidin-persistent hepatocellular carcinoma cells via ERK1/2/CREB/c-fos signaling pathway. Journal of cellular biochemistry. 2021 Jun;122(6):612-625

Mesh Tags

Substances

PMID: 33459431

search → result