Rac1 activates non-oxidative pentose phosphate pathway to induce chemoresistance of breast cancer
Rac1 activates non-oxidative pentose phosphate pathway to induce chemoresistance of breast cancer
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Rac1激活非氧化磷酸戊糖途径诱导乳腺癌化疗耐药
DOI：
10.1038/s41467-020-15308-7
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发表时间：
2020-03-19
影响因子：
16.6
通讯作者：
Hu, Hai
中科院分区：
文献类型：
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作者：
Li, Qingjian;Qin, Tao;Hu, Hai
对一种化疗药物产生耐药性往往会导致对其他化合物的获得性耐受，从而限制了癌症治疗的治疗选择。在此，我们发现，rac1的过度表达与新辅助化疗(NAC)的多药耐药有关。在机制上，rac1激活醛缩酶A和ERK信号，从而上调糖酵解，特别是非氧化戊糖磷酸途径(PPP)。这会导致核苷酸代谢增加，从而保护乳腺癌细胞免受化疗诱导的DNA损伤。为了解释这一发现，我们开发了内涵体pH响应纳米颗粒(NPs)，它可以与顺铂一起传递rac1靶向siRNA，并有效地逆转NAC耐药乳腺癌患者PDX中的NAC化疗耐药。总之，我们的发现表明，靶向rac1是克服乳腺癌获得性化疗耐药的一种潜在策略。
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.