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Rac1 activates non-oxidative pentose phosphate pathway to induce chemoresistance of breast cancer

Author

Listed:
  • Qingjian Li

    (Sun Yat-Sen University)

  • Tao Qin

    (Sun Yat-Sen University)

  • Zhuofei Bi

    (Sun Yat-Sen University)

  • Huangming Hong

    (Sun Yat-Sen University)

  • Lin Ding

    (Sun Yat-Sen University)

  • Jiewen Chen

    (Sun Yat-Sen University)

  • Wei Wu

    (Sun Yat-Sen University
    Sun Yat-Sen University)

  • Xiaorong Lin

    (Sun Yat-Sen University)

  • Wenkui Fu

    (Sun Yat-Sen University)

  • Fang Zheng

    (Sun Yat-Sen University)

  • Yandan Yao

    (Sun Yat-Sen University)

  • Man-Li Luo

    (Sun Yat-Sen University)

  • Phei Er Saw

    (Sun Yat-Sen University)

  • Gerburg M. Wulf

    (Harvard Medical School)

  • Xiaoding Xu

    (Sun Yat-Sen University)

  • Erwei Song

    (Sun Yat-Sen University
    Sun Yat-Sen University)

  • Herui Yao

    (Sun Yat-Sen University
    Sun Yat-Sen University)

  • Hai Hu

    (Sun Yat-Sen University
    Sun Yat-Sen University)

Abstract

Resistance development to one chemotherapeutic reagent leads frequently to acquired tolerance to other compounds, limiting the therapeutic options for cancer treatment. Herein, we find that overexpression of Rac1 is associated with multi-drug resistance to the neoadjuvant chemotherapy (NAC). Mechanistically, Rac1 activates aldolase A and ERK signaling which up-regulates glycolysis and especially the non-oxidative pentose phosphate pathway (PPP). This leads to increased nucleotides metabolism which protects breast cancer cells from chemotherapeutic-induced DNA damage. To translate this finding, we develop endosomal pH-responsive nanoparticles (NPs) which deliver Rac1-targeting siRNA together with cisplatin and effectively reverses NAC-chemoresistance in PDXs from NAC-resistant breast cancer patients. Altogether, our findings demonstrate that targeting Rac1 is a potential strategy to overcome acquired chemoresistance in breast cancer.

Suggested Citation

  • Qingjian Li & Tao Qin & Zhuofei Bi & Huangming Hong & Lin Ding & Jiewen Chen & Wei Wu & Xiaorong Lin & Wenkui Fu & Fang Zheng & Yandan Yao & Man-Li Luo & Phei Er Saw & Gerburg M. Wulf & Xiaoding Xu & , 2020. "Rac1 activates non-oxidative pentose phosphate pathway to induce chemoresistance of breast cancer," Nature Communications, Nature, vol. 11(1), pages 1-18, December.
    • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-15308-7
    DOI: 10.1038/s41467-020-15308-7
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