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

Abstract

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.

Cellular And Molecular Effects Of Understudied Kinase Pregnancy-Upregulated Non-Ubiquitous Calcium-Calmodulin Dependent Kinase (PNCK) In Renal Cell Carcinoma

“…Previous studies have shown that calcium calmodulin dependent kinases (CAMK1 and CAMK2) phosphorylate and activate the transcription factor (Cyclic AMP Response element binding protein) CREB at Ser133 in vitro. However, this has never been shown for PNCK [23][24][25][26]. We observed that PNCK overexpression led to increased pCREB signal, as measured by immunofluorescence (Figure 2C, F, I, L)).…”

Analysis of RHOA mutations and their significance in the proliferation and transcriptome of digestive tract cancer cells

“…CAMKK1 encodes calcium/calmodulin dependent protein kinase kinase 1 that activates calcium/calmodulin dependent protein kinase (CAMK). CAMK plays a central role in calcium/calmodulin-dependent signaling cascades implicated in cell survival and carcinogenesis ( 20 ). The genes associated with the metabolic process of small molecules which were downregulated include CYP26C1 and SLC26A1 in AGS and ACSL6 and PNLIPRP2 in SW948 cell lines.…”

Calreticulin nuclear translocalization alleviates CaM/CaMKII/CREB signaling pathway to enhance chemosensitivity in HDAC inhibitor-resistant hepatocellular carcinoma cells

“…activation [32]. These findings suggest that CaMKII-CREB is linked with differentiation, proliferation, apoptosis, and tumorigenicity; however, its role in the regulation of CRT remains unclear.…”

“…Additionally, the CaMKII is a cancer marker that is frequently overexpressed and regulates cell proliferation, survival, invasion, and migration in various cancer types [ 31 ]. Our previous study demonstrated critical roles of CaM/CaMKII-γ pathway in the apicidin-persistent HCC prosurvival capability via ERK1/2/CREB/c-fos signaling activation [ 32 ]. These findings suggest that CaMKII-CREB is linked with differentiation, proliferation, apoptosis, and tumorigenicity; however, its role in the regulation of CRT remains unclear.…”