Blockade of GRP78 sensitizes breast cancer cells to microtubules-interfering agents that induce the unfolded protein response

Taxane and vinblastine represent two classes of microtubules-targeted agents for cancer chemotherapy. Although taxol and vinblastine are widely used for cancer treatment, resistance to these agents is frequently encountered in the clinic. An ongoing question has been what mechanisms are involved in the resistance of tumour cells to microtubules-targeted agents or how the clinical effectiveness can be improved. There is increasing evidence that microtubules interact with the endoplasmic reticulum (ER). Here, we have shown that taxol and vinblastine induce multiple arms of the ER stress response, including up-regulation of glucose-regulated protein 78 (GRP78) expression, X-box binding protein 1 splicing and eukaryotic initiation factor 2 alpha phosphorylation. Abrogation of GRP78 induction sensitizes breast cancer cells to taxol and vinblastine. Treatment with (-)-epigallocatechin gallate (EGCG), a known GRP78 inhibitor, synergistically promotes taxol- and vinblastine-induced cell death. GRP78 knockdown or EGCG potentiates taxol- and vinblastine-induced activation of pro-apoptosis arms of the ER stress response, such as JNK phosphorylation, caspase-7 and PARP cleavage. Inhibition of JNK and caspase-7 abrogates EGCG sensitization of breast cancer cells to taxol and vinblastine. We conclude that induction of the unfolded protein response represents a novel mechanism underlying the efficacy and resistance to microtubules-targeted agents. Combination of compounds capable of suppressing GRP78 might be a novel approach for improving the effectiveness of microtubules-targeted chemotherapy.