62P - PKCα crosstalk with GSTP1 and Bcl2 mediates therapeutic response in breast cancer
|Date||08 May 2014|
|Session||Welcome reception and Poster Walk|
|Topics|| Breast Cancer
|Citation||Annals of Oncology (2014) 25 (suppl_1): i21-i22. 10.1093/annonc/mdu069|
Two major factors underlying the poor therapeutic outcome of breast cancer are the intrinsic drug resistance and the abnormalities that drive the growth of breast tumours. Elevated levels of serine/threonine kinase PKC is frequently observed in breast tumours and linked with cancer progression and more aggressive phenotype. GSTP1, a major phase II drug metabolizing and cell signaling protein has been associated with drug resistance and poor patient survival. Recently, GSTP1 protein was recognized as a downstream target of PKC family of isoforms. We demonstrated that GSTP1 undergoes phosphorylation by PKC, resulting in a significant enhancement of its metabolic activity and increased protein half-life. The contribution of PKC-dependent post-translational modification of GSTP1 to drug resistance was investigated using cisplatin as a prototype drug and assessed by directly measuring levels of glutathionylplatinum and cytotoxic cisplatin-DNA interstrand cross-links, residual free cisplatin and modulation of JNK signaling. The results showed that serine phosphorylation of GSTP1 correlate significantly with decreased free cisplatin, decreased DNA interstrand cross-links and increased resistance to cisplatin. Additionally, although cisplatin treatment activated JNK in tumour cells, the levels of activation were significantly greater following siRNA-mediated GSTP1 knockdown. Suppression of GSTP1 or PKC, individually and in combination, confirmed the GSTP1 dependency of the effects of PKC activation on the endpoints of cisplatin toxicity in the cells and breast tumour xenografts. Further, PKC-mediated serine phosphorylation of anti-apoptotic protein Bcl2 prolongs its half-life and decreases activation of caspase-3 in breast cancer cells. Both in vitro and in vivo studies suggest that phosphorylation of GSTP1 during drug treatment can alter the balance of regulation of JNK and Bcl2 signaling pathways that influence cell proliferation and apoptosis, thereby conferring on breast cancer cells the ability to escape death . Our findings provide important insights into the cellular pathways mediated by PKC and are likely to lead to novel therapeutic strategies for breast cancer, particularly those characterized by high PKC expression and elevated or highly activated GSTP1 and Bcl2.
All authors have declared no conflicts of interest.