Open AccessBlockade of GRP78 sensitizes breast cancer cells to microtubules‐interfering agents that induce the unfolded protein response
Author(s) -
Wang Jiao,
Yin Yancun,
Hua Hui,
Li Minjing,
Luo Ting,
Xu Li,
Wang Ranran,
Liu Dongbo,
Zhang You,
Jiang Yangfu
Publication year - 2009
Publication title -
journal of cellular and molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.44
H-Index - 130
eISSN - 1582-4934
pISSN - 1582-1838
DOI - 10.1111/j.1582-4934.2009.00873.x
Subject(s) - vinblastine , unfolded protein response , endoplasmic reticulum , cancer research , microtubule , cancer cell , microbiology and biotechnology , medicine , biology , cancer , chemotherapy
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 2α 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.