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LIVER AND BILIARY TRACT

Increasing cell membrane potential and GABAergic activity inhibits malignant hepatocyte growth

Departments of ¹Medicine and ²Pathology, Liver Diseases Unit, University of Manitoba, Winnipeg, Manitoba, Canada R3E 3P4

Submitted 3 December 2002 ; accepted in final form 13 March 2003

Increasing hepatocyte membrane potentials by augmenting GABAergic activity inhibits nonmalignant hepatocyte proliferative activity. The objectives of this study were to document 1) potential differences (PDs) of four malignant hepatocyte cell lines, 2) GABA_A receptor mRNA expression in the same cell lines, and 3) effects of restoring malignant hepatocyte PDs to levels approximating those of resting, nonmalignant hepatocytes. Hepatocyte PDs were documented in nonmalignant and malignant (Chang, HepG2, HuH-7, and PLC/PRF/5) hepatocytes with a fluorescent voltage-sensitive dye and GABA_A receptor expression by RT-PCR and Western blot analyses. Compared with nonmalignant human hepatocytes, all four malignant cell lines were significantly depolarized (P < 0.0001, respectively). Only PLC/PRF/5 cells had detectable GABA_A-₃ receptor mRNA expression and all cell lines were negative for GABA_A-₃ receptor protein by Western blot analysis. Stable transfection of Chang cells with GABA_A-₃ receptor cDNA resulted in significant increases in PD and decreases in proliferative activity as manifest by decreased [³H]thymidine and bromodeoxyurieine incorporation rates, 4-[3-(4-lodophenyl)-2-(4-nitrophenyl)-2H-5-tetrazolio]-1,3-benzene disulfonate activity, a lower mitotic index, prolongation of cell-doubling times, and attenuated growth patterns compared with cells transfected with vector alone. Colony formation in soft agar and the number of abnormal mitoses were also significantly decreased in GABA_A-₃ receptor transfected cells. The results of this study indicate 1) relative to healthy hepatocytes, malignant hepatocytes are significantly depolarized, 2) GABA_A-₃ receptor expression is absent in malignant hepatocyte cell lines, and 3) increasing the PD of malignant hepatocytes is associated with less proliferative activity and a loss of malignant features.

cancer; regeneration; membrane potential; proliferation, differentiation, liver disease, hepatocellular carcinoma

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