The calcium channel agonist Bay K 8644 promotes the growth of human liver cancer HepG2 cells in vitro: suppression with overexpressed regucalcin

• Published in: Molecular and cellular biochemistry 2020-09, Vol.472 (1-2), p.173-185
• Main Authors: Yamaguchi, Masayoshi, Murata, Tomiyasu, Ramos, Joe W.
• Format: Article
• Language: English
• Subjects: 3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester - adverse effects; Agonists; Apoptosis; Biochemistry; Biomedical and Life Sciences; Calcium (intracellular); Calcium antagonists; Calcium Channel Agonists - adverse effects; Calcium channels; Calcium channels (L-type); Calcium Channels, L-Type - chemistry; Calcium homeostasis; Calcium ions; Calcium signalling; Calcium-Binding Proteins - genetics; Calcium-Binding Proteins - metabolism; Carcinoma, Hepatocellular - etiology; Carcinoma, Hepatocellular - metabolism; Carcinoma, Hepatocellular - pathology; Carcinoma, Hepatocellular - prevention & control; Cardiology; Cell death; Cell growth; Cell Proliferation; Death; Ethylenediaminetetraacetic acid; Gene expression; Gene regulation; Genetic aspects; Growth; Health aspects; Hepatocellular carcinoma; Hepatocytes; Homeostasis; Humans; In Vitro Techniques; Intracellular Signaling Peptides and Proteins - genetics; Intracellular Signaling Peptides and Proteins - metabolism; Intracellular signalling; Kinases; Life Sciences; Liver; Liver cancer; Liver Neoplasms - etiology; Liver Neoplasms - metabolism; Liver Neoplasms - pathology; Liver Neoplasms - prevention & control; MAP kinase; Medical Biochemistry; Mortality; Oncology; Protein kinase; Protein kinases; Signaling; Thapsigargin; Transcription; Tumor Cells, Cultured; Tumors; Verapamil; Wortmannin
• ISSN: 0300-8177; 1573-4919; 1573-4919
• DOI: 10.1007/s11010-020-03795-7

Hepatocellular carcinoma is one of the most prevalent malignant diseases and causes a third of cancer-related death. The consequences of altered calcium homeostasis in cancer cells may contribute to tumor progression. Regucalcin plays an inhibitory role in calcium signaling linked to transcription regulation. Regucalcin gene expression is downregulated in the tumor tissues of liver cancer patients, suggesting an involvement as a suppressor in hepatocarcinogenesis. We investigated whether Bay K 8644, an agonist of the L-type Ca 2+ channel, promotes the growth of human liver cancer and if the effect of Bay K 8644 is suppressed by overexpressed regucalcin using the HepG2 cell model. The colony formation and growth of HepG2 cells were promoted by culturing with Bay K 8644 (0.1–10 nM). This effect was suppressed by inhibitors of signaling processes linked to cell proliferation, including PD98059 and wortmannin. Death of HepG2 cells was stimulated by Bay K 8644 with higher concentrations (25 and 100 nM). The effects of Bay K 8644 on cell growth and death were abolished by verapamil, an antagonist of calcium channel. Mechanistically, culturing with Bay K 8644 increased levels of mitogen-activated protein kinase (MAPK) and phospho-MAPK. Notably, overexpressed regucalcin suppressed Bay K 8644-promoted growth and death of HepG2 cells. Furthermore, overexpressed regucalcin prevented growth and increased death induced by thapsigargin, which induces the release of intracellular stored calcium. Thus, higher regucalcin expression suppresses calcium signaling linked to the growth of liver cancer cells, providing a novel strategy in treatment of hepatocellular carcinoma with delivery of the regucalcin gene.