• Open Access

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

Authors

  • Jiao Wang,

    1. Division of Signal Transduction and Molecular Targeted Therapy, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China
    2. School of Basic Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, China
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    • These authors contributed equally to this work.

  • Yancun Yin,

    1. Division of Signal Transduction and Molecular Targeted Therapy, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China
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    • These authors contributed equally to this work.

  • Hui Hua,

    1. Division of Signal Transduction and Molecular Targeted Therapy, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China
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  • Minjing Li,

    1. Division of Signal Transduction and Molecular Targeted Therapy, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China
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  • Ting Luo,

    1. Division of Signal Transduction and Molecular Targeted Therapy, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China
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  • Li Xu,

    1. Division of Signal Transduction and Molecular Targeted Therapy, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China
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  • Ranran Wang,

    1. Division of Signal Transduction and Molecular Targeted Therapy, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China
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  • Dongbo Liu,

    1. Division of Signal Transduction and Molecular Targeted Therapy, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China
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  • You Zhang,

    1. Division of Signal Transduction and Molecular Targeted Therapy, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China
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  • Yangfu Jiang

    Corresponding author
    1. Division of Signal Transduction and Molecular Targeted Therapy, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China
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Correspondence to: Yangfu JIANG, Ph.D., State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, No.1 Ke Yuan 4 Lu, Chengdu 610041, China.
Tel.: 86-28-81812821
E-mail: jyangfu@scu.edu.cn

Abstract

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.

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