Developing Inhibitors of Ovarian Cancer Progression by Targeted Disruption of the Gamma-Synuclein Activated Migratory and Survival Signaling Pathways

摘要

Synucleins are a family of highly conserved small proteins that are normally expressed predominantly in neurons. Very little is known about the physiological functions of rhe synucleins. We have reported that y-synuclein (also known as BCSGI) is dramatically up regulated in the vast majority (>70%) of late-stage breast and ovarian cancers (Bruening, et al., 2000). When overexpressed, ysynuclein significantly stimulates cell proliferation and metastasis in some breast cancer cell lines. We have shown that DNA hypomethylation is a common mechanism underlying the abnormal expression of this gene in tumor cells (Gupta et al., 2003) and hypothesize that y-synuclein may be a proto-oncogene and that abberant expression of this protein may contribute to the development and progression of ovarian cancer. We also found that y-synuclein can promote cancer cell survival and inhibit stress- and chemotherapy drug-induced apoptosis by modulating MAPKs. Specifically, overexpression of y-synuclein lead to constitutive activation of ERK112, and down-regulation of JNKl in response to a host of environmental stress signals, including W, heat shock, sodium arsenete, nitric oxide and chemotherapeutic drugs (Pan, Z-2, et nl., 2002). Because of its high frequency of expression in late-stage ovarian cancers, we hypothesized that y-synuclein may be a promising target for cancer therapy.