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- Title
Rac1 activates non-oxidative pentose phosphate pathway to induce chemoresistance of breast cancer.
- Authors
Li, Qingjian; Qin, Tao; Bi, Zhuofei; Hong, Huangming; Ding, Lin; Chen, Jiewen; Wu, Wei; Lin, Xiaorong; Fu, Wenkui; Zheng, Fang; Yao, Yandan; Luo, Man-Li; Saw, Phei Er; Wulf, Gerburg M.; Xu, Xiaoding; Song, Erwei; Yao, Herui; Hu, Hai
- 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. Acquired resistance to chemotherapy can lead to multi-drug resistance and poor prognosis in cancer. Here, the authors show that Rac1 increases glycolysis and non-oxidative pentose phosphate pathway activity leading to neoadjuvant chemotherapy (NAC) resistance, thus its inhibition sensitizes resistant breast cancer PDXs to NAC.
- Subjects
PENTOSE phosphate pathway; DRUG resistance in cancer cells; BREAST cancer; GLYCOLYSIS; MULTIDRUG resistance; DNA damage
- Publication
Nature Communications, 2020, Vol 11, Issue 1, p1
- ISSN
2041-1723
- Publication type
Article
- DOI
10.1038/s41467-020-15308-7