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Originally published In Press as doi:10.1074/jbc.M201650200 on July 16, 2002

J. Biol. Chem., Vol. 277, Issue 38, 35050-35060, September 20, 2002
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gamma -Synuclein Promotes Cancer Cell Survival and Inhibits Stress- and Chemotherapy Drug-induced Apoptosis by Modulating MAPK Pathways*

Zhong-Zong PanDagger §, Wendy Bruening||, Benoit I. Giasson**Dagger Dagger , Virginia M.-Y. Lee**, and Andrew K. GodwinDagger §§

From the Dagger  Department of Medical Oncology, Fox Chase Cancer Center, Philadelphia, Pennsylvania 19111 and the ** Center for Neurodegenerative Diseases, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104

Synucleins are a family of highly conserved small proteins predominantly expressed in neurons. Recently we and others have found that gamma -synuclein is dramatically up-regulated in the vast majority of late-stage breast and ovarian cancers and that gamma -synuclein over-expression can enhance tumorigenicity. In the current study, we have found that gamma -synuclein is associated with two major mitogen-activated kinases (MAPKs), i.e. extracellular signal-regulated protein kinases (ERK1/2) and c-Jun N-terminal kinase 1 (JNK1), and have shown that over-expression of gamma -synuclein leads to constitutive activation of ERK1/2 and down-regulation of JNK1 in response to a host of environmental stress signals, including UV, arsenate, and heat shock. We also tested the effects of gamma -synuclein on apoptosis and activation of JNK and ERK in response to several chemotherapy drugs. We have found that gamma -synuclein-expressing cells are significantly more resistant to the chemotherapeutic drugs paclitaxel and vinblastine as compared with the parental cells. The resistance to paclitaxel can be partially obliterated when ERK activity is inhibited using a MEK1/2 inhibitor. Activation of JNK and its downstream caspase-3 by paclitaxel or vinblastine is significantly down-regulated in gamma -synuclein-expressing cells, indicating that the paclitaxel- or vinblastine-activated apoptosis pathway is blocked by gamma -synuclein. In contrast to paclitaxel and vinblastine, etoposide does not activate JNK, and gamma -synuclein over-expression has no apparent effect on this drug-induced apoptosis. Taken together, our data indicate that oncogenic activation of gamma -synuclein contributes to the development of breast and ovarian cancer by promoting tumor cell survival under adverse conditions and by providing resistance to certain chemotherapeutic drugs.

* This work was supported in part by the Eileen Stein-Jacoby Fund, the Ovarian Cancer Research Fund, a concept grant from the Department of Defense (DAMD17-01-1-0522), a grant from the National Institutes of Health (Ovarian Cancer SPORE P50 CA83638), and by an appropriation from the Commonwealth of Pennsylvania.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

§ Supported by a fellowship from the Department of Defense (Institutional Breast Cancer Training Program grant DAMD17-00-1-0249).

Present address: Health Technology Assessment Information Service, Plymouth Meeting, PA 19462.

|| Supported by a fellowship from the National Institutes of Health.

Dagger Dagger Supported by a fellowship from the Human Frontiers Foundation.

§§ To whom correspondence should be addressed: Dept. of Medical Oncology, Fox Chase Cancer Center, 7701 Burholme Ave., Rm. W322, Philadelphia, PA 19111. Tel.: 215-728-2205; Fax: 215-728-2741; E-mail: A_Godwin@fccc.edu.

Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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