Gamma Synuclein Promotes a Metastatic Phenotype in Breast Cancer and Ovarian Tumor Cells by Modulating the Rho Signal Transduction Pathway
Abstract
Synucleins(a, b, g, synoretin) are a family of small, highly conserved proteins expressed predominantly in neurons. While a-synuclein is implicated in neurodegenerative diseases, g-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 g-synuclein and its role in the malignancy of breast and ovarian cancer, we ectopically overexpressed g-synuclein in several cancer cell lines. Recently we found that g-synuclein is associated with two major mitogen-activated kinases (MAPK), i.e., extracellular signal-regulated protein kinases (ERK 1/2) and c-Jun N-terminal kinase 1 (JNKl). Over-expression of g-synuclein lead to constitutive activation of ERKl/2, and down-regulation of JNKl in response to stress (UV, sodium arsenate, and heat shock). In this study, we further characterized the effects of g-synuclein on paclitaxel, a commonly used chemotherapeutic drug, and nitric oxide induced apotosis. We found that g-synuclein over%expressing cells were more resistant (4- to 5-fold) to paclitaxel or nitric oxided as compared to the parental cells. This resistance to paclitaxel could be partially restored when ERK activity was inhibited using U0126, a MEKl/2 inhibitor. In addition, activation of the mitochodrial apoptotic pathway (JNK and/or caspase 3 activation) by paclitaxel and nitric oxide was blocked by ectopic expression of g-synuclein. Collectively, these data indicate that g-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. Because of its high frequency of expression in late-stage breast and ovarian cancers, g-synuclein may be a promising target for therapy.
Document Details
- Document Type
- Technical Report
- Publication Date
- May 01, 2003
- Accession Number
- ADA417957
Entities
People
- Andrew K. Godwin
Organizations
- Fox Chase Cancer Center