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Nodal Induces Apoptosis and Inhibits Proliferation in Human Epithelial Ovarian Cancer Cells via Activin Receptor-Like Kinase 7

Department of Biology (G.X., Y.Z., S.M., C.P.), York University, Toronto, Ontario M3J 1P3, Canada; Sunnybrook and Women’s College Health Science Centre and Department of Laboratory Medicine and Pathobiology (B.B.Y.), University of Toronto, Toronto, Canada M4N 3M5; Department of Obstetrics and Gynaecology and Cellular and Molecular Medicine (B.K.T.), University of Ottawa, and Hormones, Growth and Development Program, Ottawa Health Research Institute, Ottawa, Canada K1Y 4E9

Address all correspondence and requests for reprints to: Dr. Chun Peng, Department of Biology, York University, 4700 Keel Street, Toronto, Ontario, Canada M3J 1P3. E-mail: cpeng{at}yorku.ca.

Human epithelial ovarian cancer is the most lethal female cancer. Hormones and growth factors, including the TGF-ß superfamily, have been suggested to play a role in ovarian tumorigenesis. The biological effects of TGF-ß superfamily are mediated by type I and type II serine/threonine kinase receptors and by intracellular Smad proteins. Recently, we have cloned four transcripts of human activin receptor-like kinase 7 (ALK7), a type I receptor for Nodal. In this study, we have investigated the role of Nodal and ALK7 in four ovarian cancer cell lines, OV2008, C13*, A2780-s, and A2780-cp. Overexpression of Nodal resulted in a significant decrease in the number of metabolically active cells. This effect was mimicked by a constitutively active ALK7 (ALK7-ca) but blocked by dominant negative mutants of ALK7, Smad2, or Smad3. Transient transfection of Nodal and ALK7-ca significantly decreased X-linked inhibitor of apoptosis protein (Xiap) expression, activated both caspase-3 and caspase-9, and increased apoptosis as determined by Hoechst nuclear staining and flow cytometry. In addition, Nodal and ALK7-ca also inhibited cell proliferation as measured by 5-bromo-2'-deoxyuridine (BrdU) assays. Interestingly, the effects of Nodal and ALK7-ca were more potent in chemosensitive A2780-s cells than in its chemoresistant counterpart, A2780-cp cells. These findings demonstrate that Nodal induces apoptosis and inhibits proliferation via ALK7 and Smad2/3 and that the effect of Nodal-ALK7 on apoptosis may be mediated in part by the down-regulation of Xiap and activation of caspase-9 and caspase-3.

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