Synuclein-gamma (SNCG) plays oncogenic roles in breast
carcinogenesis. Although the expression of SNCG is abnormally high in advanced and metastatic
breast carcinomas, SNCG is not expressed in normal or benign breast tissues. SNCG is an
intrinsically disordered protein known to interact with BubR1, a mitotic checkpoint
kinase. The SNCG-BubR1 interaction inhibits mitotic checkpoint control upon spindle damage caused by anticancer drugs, such as
nocodazole and
taxol. Antimicrotubule drugs that cause mitotic arrest and subsequent apoptosis of
cancer cells are frequently used to treat
breast cancer patients with advanced or metastatic diseases. However, patient response rates to this class of chemotherapeutic agents vary significantly. In this study, we have designed a novel
peptide (ANK) and shown its interaction with SNCG using fluorometry, surface plasmon resonance, and isothermal titration calorimetry. Binding of the ANK
peptide did not induce folding of SNCG, suggesting that SNCG can function biologically in its intrinsically disordered state. Microinjection of the ANK
peptide in
breast cancer cell line overexpressing SNCG (MCF7-SNCG) exhibited a similar cell killing response by
nocodazole as in the SNCG-negative MCF7 cells. Overexpression of
enhanced green fluorescent protein-tagged ANK reduces SNCG-mediated resistance to
paclitaxel treatment by approximately 3.5-fold. Our coimmunoprecipitation and colocalization results confirmed the intracellular association of the ANK
peptide with SNCG. This is likely due to the disruption of the interaction of SNCG with BubR1 interaction. Our findings shed light on the molecular mechanism of the ANK
peptide in releasing SNCG-mediated drug resistance.