Gamma Synuclein Promotes a Metastatic Phenotype in Breast and Ovarian Tumor Cells by Modulating the Rho Signal Transduction Activity

摘要

The synucleins (alpha, beta, gamma synoretin) are a family of small, highly conserved proteins expressed predominantly in neurons. While alpha- synuclein is implicated neurodegenerative diseases, gamma-synuclein is expressed in the majority (>85%) of late-stage breast and ovarian carcinomas and is not expressed in normal mammary and ovarian epithelium. In spite of their significance, the normal and pathological roles of synucleins are not fully understood. To address the biological function of gamma-synuclein and its role in the malignancy of breast and ovarian cancer, we ectopically over-expressed gamma-synuclein in several cancer cell lines. Recently we found that gamma- synuclein is associated with two major mitogen-activated kinases (MAPK), i.e., extracellular signal-regulated protein kinases (ERK1/2) and c-Jun N-terminal kinase 1 (JNK1). Over-expression of gamma-synuclein lead to constitutive activation of MERK1/2, and down-regulation of JNK1 in response to stress (UV, sodium arsenate, and heat shock). In this study, we further characterized the effects of gamma-synuclein on paclitaxel, a commonly used chemotherapeutic drug, and nitric oxide induced apotosis. We found that gamma-synuclein over-expressing cells were more resistant (4- to 5-fold) to paclitaxel or nitric oxide as compared to the parental cells. This resistance to paclitaxel could be partially restored when ERK activity was inhibited using U0126, a MEK1/2 inhibitor. In addition, activation of the mitochondrial apoptotic pathway (JNK and/or caspase 3 activation) by paclitaxel and nitric oxide was blocked by ectopic expression of gamma-synuclein. Collectively, these data indicate that gamma-synuclein may be involved in the pathogenesis of breast and ovarian cancer by promoting tumor cell survival under adverse conditions and by providing resistance to certain anti-cancer drugs.