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Nodal induces apoptosis and inhibits proliferation in human epithelial ovarian cancer cells via activin receptor-like kinase 7.
J Clin Endocrinol Metab. 2004 Nov; 89(11):5523-34.JC

Abstract

Human epithelial ovarian cancer is the most lethal female cancer. Hormones and growth factors, including the TGF-beta superfamily, have been suggested to play a role in ovarian tumorigenesis. The biological effects of TGF-beta 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.

Authors+Show Affiliations

Department of Biology, York University, 4700 Keel Street, Toronto, Ontario, Canada M3J 1P3.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

15531507

Citation

Xu, Guoxiong, et al. "Nodal Induces Apoptosis and Inhibits Proliferation in Human Epithelial Ovarian Cancer Cells Via Activin Receptor-like Kinase 7." The Journal of Clinical Endocrinology and Metabolism, vol. 89, no. 11, 2004, pp. 5523-34.
Xu G, Zhong Y, Munir S, et al. Nodal induces apoptosis and inhibits proliferation in human epithelial ovarian cancer cells via activin receptor-like kinase 7. J Clin Endocrinol Metab. 2004;89(11):5523-34.
Xu, G., Zhong, Y., Munir, S., Yang, B. B., Tsang, B. K., & Peng, C. (2004). Nodal induces apoptosis and inhibits proliferation in human epithelial ovarian cancer cells via activin receptor-like kinase 7. The Journal of Clinical Endocrinology and Metabolism, 89(11), 5523-34.
Xu G, et al. Nodal Induces Apoptosis and Inhibits Proliferation in Human Epithelial Ovarian Cancer Cells Via Activin Receptor-like Kinase 7. J Clin Endocrinol Metab. 2004;89(11):5523-34. PubMed PMID: 15531507.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Nodal induces apoptosis and inhibits proliferation in human epithelial ovarian cancer cells via activin receptor-like kinase 7. AU - Xu,Guoxiong, AU - Zhong,Yu, AU - Munir,Sadia, AU - Yang,Burton B, AU - Tsang,Benjamin K, AU - Peng,Chun, PY - 2004/11/9/pubmed PY - 2004/12/16/medline PY - 2004/11/9/entrez SP - 5523 EP - 34 JF - The Journal of clinical endocrinology and metabolism JO - J. Clin. Endocrinol. Metab. VL - 89 IS - 11 N2 - Human epithelial ovarian cancer is the most lethal female cancer. Hormones and growth factors, including the TGF-beta superfamily, have been suggested to play a role in ovarian tumorigenesis. The biological effects of TGF-beta 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. SN - 0021-972X UR - https://www.unboundmedicine.com/medline/citation/15531507/Nodal_induces_apoptosis_and_inhibits_proliferation_in_human_epithelial_ovarian_cancer_cells_via_activin_receptor_like_kinase_7_ L2 - https://academic.oup.com/jcem/article-lookup/doi/10.1210/jc.2004-0893 DB - PRIME DP - Unbound Medicine ER -