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.