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Calmodulin/CaMKII‐γ mediates prosurvival capability in apicidin‐persistent hepatocellular carcinoma cells via ERK1/2/CREB/c‐fos signaling pathway
Author(s) -
Hsu WeiChung,
Le HangNga,
Lin YuJung,
Chen MingCheng,
Wang TsoFu,
Li ChiCheng,
Kuo WeiWen,
Mahalakshmi B.,
Singh Chaouhan Hitesh,
Chen MeiChih,
Huang ChihYang
Publication year - 2021
Publication title -
journal of cellular biochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.028
H-Index - 165
eISSN - 1097-4644
pISSN - 0730-2312
DOI - 10.1002/jcb.29892
Subject(s) - creb , calmodulin , cancer research , signal transduction , microbiology and biotechnology , biology , protein kinase a , kinase , transcription factor , biochemistry , gene , enzyme
Calmodulin (CaM), a Ca 2+ binding protein, plays a critical role in cancer initiation and progression through binding and activating numerous target proteins, including Ca 2+ /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.