Volume-sensitive chloride channels associated with human cervical carcinogenesis

Previous controversy has risen from the purported equivalence of the volume-sensitive chloride channels with P-glycoprotein. The aim of this study was to investigate the association between expression of volume-sensitive Cl- channels and the process of malignant transformation of cervical epithelial cells. We studied the activations of volume-sensitive and cAMP-mediated chloride currents in various human cervical squamous cells that were representative of different stages of cervical carcinogenesis, i.e., normal cervical epithelium, low-grade cervical intraepithelial neoplasia, carcinoma in situ, and invasive carcinoma using the whole-cell patch clamp technique. The volume-sensitive chloride channels, however, were significantly activated only in the four cervical cancer cell lines, primary culture cells of carcinoma in situ, and invasive cancer of the cervix. The expression of volume-sensitive chloride currents was independent of the state of human papillomavirus positivity. When these cells were exposed to hypotonic shock, the cells swelled, and outward rectified chloride currents were observed. These effects were readily reversed by returning the cells to isotonic medium. In addition, 4,4'-diisothiocyanatostilbene-2,2-disulfonic acid, 1,9-dideoxyforskolin, and verapamil reversibly abolished the volume-sensitive Cl- currents. In contrast, none of the cells from normal cervices and human papillomavirus-immortalized cell lines, the in vitro equivalent of low-grade cervical intraepithelial neoplasia, developed substantial chloride currents on exposure to hypotonicity. cAMP-mediated chloride currents were ubiquitously activated in all cervical squamous cells, regardless of the stages of carcinogenesis. This is the first report suggesting an in vivo association between the development of volume-sensitive chloride currents and human carcinogenesis.