ºÚÁÏÍø

Abstract

Breast cancer is the most prevalent cancer in women. Tamoxifen (TAM) has been used for several years as an effective drug for treating estrogen receptor positive breast tumors. However, resistance to TAM is a major challenge in treatment of breast cancer. Accumulating evidence has highlighted the role of Glucose-regulated protein (GRP)-78, the master regulator of the unfolded protein response, in chemoresistance. The present study aimed to decipher the function of GRP78 during response to TAM in breast cancer cells. Among a panel of drugs -paclitaxel, doxorubicin, 5-fluorouracil, UCN-01 and tamoxifen, only TAM induced apoptosis and up-regulated the expression of GRP78 in MCF-7 and MDA-MB-231 cell lines. Inhibition of GRP78 augmented apoptosis and overexpression rendered the cells resistant suggesting a decisive role for GRP78 in TAMmediated cytotoxicity. Mechanistically, TAM selectively unregulated phosphorylation of Akt on Thr308 but not on Ser473, and silencing of GRP78 resulted in inhibition of Akt (Thr308) phosphorylation. GRP78 inhibition prevented TAM-induced phosphorylation of GSK3�², a downstream substrate of Akt implicating a role for GRP78 in TAM-induced Akt activation. Additionally, our study demonstrated a physical association of Akt and GRP78 that may be decisive for cell survival. The present study identifies a crucial role for GRP78 and Akt-mediated survival mechanism during TAM-induced response in breast cancer cells. The findings provide evidence for the protective function of GRP78 in stressed cells to promote drug resistance and suggest that a combination of compounds targeting GRP78 and anticancer drugs like TAM would be beneficial to overcome therapy resistance.

Biography

Email: radhapujari@gmail.com