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J. Biol. Chem., Vol. 279, Issue 51, 53087-53096, December 17, 2004

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Cyr61 Suppresses Growth of Human Endometrial Cancer Cells^*

Wenwen Chien, Takashi Kumagai, Carl W. Miller, Julian C. Desmond, Jonathan M. Frank, Jonathan W. Said, and H. Phillip Koeffler

From the Department of Hematology/Oncology, Cedars-Sinai Research Institute, UCLA School of Medicine, Los Angeles, California 90048

Cyr61 (CCN1) is a member of the CCN protein family; these secreted proteins are involved in diverse biological processes such as cell adhesion, angiogenesis, apoptosis, and either growth arrest or growth stimulation depending on the cellular context. We studied the role of Cyr61 in endometrial tumorigenesis. Levels of Cyr61 were decreased in endometrial tumors compared with normal endometrium. Knockdown of Cyr61 expression by RNA interference in a well differentiated endometrial adenocarcinoma cell line (Ishikawa) stimulated its cellular growth. Conversely, overexpression of the protein in the undifferentiated AN3CA endometrial cancer cell line decreased their growth concurrently with increased apoptosis in liquid culture. These same cells had decreased clonogenic capacity and a nearly complete loss of tumorigenicity in vivo. Furthermore, partially purified Cyr61 suppressed growth of endometrial cancer cells. The increased apoptosis in these endometrial cancer cells with forced overexpression of Cyr61 was associated with elevated expression of the pro-apoptotic proteins Bax, Bad, and TRAIL (tumor necrosis factor receptor-associated ligand). Cyr61-induced caspase-3 activation and depolarization of mitochondrial membrane. In summary, endometrial cancer cells have decreased expression of Cyr61 compared with normal endometrium, and this lowered expression may provide the transformed cells a growth advantage over their normal counterpart.

Received for publication, September 7, 2004

^* This research was supported in part by grants from the National Institutes of Health, Women's Cancer Research Institute at Cedars-Sinai Medical Center, The Sid and Ann Schwartz Family Funds, as well as the Tom Collier Cancer Fund. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Holds the Mark Goodson Chair in Oncology Research and is a member of the Molecular Biology Institute and Jonsson Cancer Center of UCLA.

To whom correspondence should be addressed: Dept. of Hematology/Oncology, Cedars-Sinai Medical Center, 110 George Burns Rd., D5065, Los Angeles, CA 90048. Tel.: 310-423-7759; Fax: 310-423-0225; E-mail: chienw{at}ucla.edu.

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