Tumor suppression by a proapoptotic calcium-activated chloride channel in mammary epithelium.
Little is known of the roles played by ion channels in cancer. Here we describe a pair of closely related calcium-activated chloride channels whose differential regulation in normal, apoptotic, and transformed mouse cells suggests that channel function is proapoptotic and antineoplastic. While mCLCA1 predominates over mCLCA2 under normal physiological conditions, this relationship is reversed by apoptotic stress both in developing mammary gland and in cultured HC11 mammary epithelial cells. Consistent with an apoptosis-promoting role, splicing of mCLCA2 is disrupted in apoptosis-resistant tumor cell lines and in HC11 cells selected for resistance to detachment-induced apoptosis (anoikis). Unexpectedly, mCLCA1 message is also down-regulated in these cells by at least 30-fold. These results suggest that both genes antagonize survival of mammary tumor cells by sensitizing them to anoikis. When MCF7 or HEK293 tumor cells were transfected with plasmids encoding either mCLCA1 or mCLCA2, colony formation was greatly reduced relative to a vector-transfected control, demonstrating that calcium-sensitive chloride channel (CLCA) expression is deleterious to tumor cell survival. Furthermore, mammary epithelial cells overexpressing mCLCA2 had twice the rate of apoptosis of normal cells when subjected to serum starvation and formed multinuclear giants at a high frequency in normal culture, suggesting that mCLCA2 can promote either apoptosis or senescence.
Elble
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RC
Cancer Biology Laboratories and Department of Molecular Medicine, Cornell University College of Veterinary Medicine, Ithaca, New York 14853, USA. rce3@cornell.edu
Pauli
B U
BU
D000595:Amino Acid Sequence; D017209:Apoptosis; D001483:Base Sequence; D002118:Calcium / Q000378:metabolism*; D002460:Cell Line; D018118:Chloride Channels / Q000235:genetics / Q000378:metabolism*; D003001:Cloning, Molecular; D017931:DNA Primers; D004847:Epithelial Cells / Q000378:metabolism; D006801:Humans; D008321:Mammary Glands, Animal / Q000166:cytology / Q000378:metabolism*; D008969:Molecular Sequence Data; D017386:Sequence Homology, Amino Acid; D014407:Tumor Cells, Cultured
C120066:CLCA2 protein, human; D018118:Chloride Channels; C492299:Clca2 protein, mouse; D017931:DNA Primers; D002118:Calcium