Inhibition of HSP90 sensitizes a novel Raf/ERK dual inhibitor CY-9d in triple-negative breast cancer cells
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Yujuan Chen1,*, Xiaoyun Wang1,*, Chuan Cao2, Xiaodong Wang1, Shufang Liang1, Cheng Peng2, Leilei Fu1 and Gu He1
1State Key Laboratory of Biotherapy and Department of Breast Surgery, West China Hospital, West China Medical School, Sichuan University and Collaborative Innovation Center for Biotherapy, Chengdu 610041, China
2State Key Laboratory Breeding Base of Systematic Research Development and Utilization of Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China
*These authors have contributed equally to this work
Xiaodong Wang, email: [email protected]
Leilei Fu, email: [email protected]
Gu He, email: [email protected]
Keywords: breast cancer; Raf; ERK; HSP90; apoptosis
Received: August 09, 2017 Accepted: September 22, 2017 Published: October 26, 2017
Raf and extracellular signal-regulated kinases (ERK) are both important therapeutic targets in the mitogen-activated protein kinase (MAPK) pathway, and play crucial roles in the apoptosis resistance of breast cancer cells. In the present study, cytotoxic and apoptosis-inducing activities of the Raf/ERK dual inhibitor CY-9d were found to be restricted in triple negative breast cancer (TNBC) cells compared with ER/PR-positive cells. Based on the analysis of differentially expressed proteins using a quantitative proteomic iTRAQ method and bioinformatics analysis, HSP90 was found to identify as a potential mediator between Raf and ERK in TNBC cells. Western blotting and RNA interference suggested that down-regulated IQGAP1 can attenuate the routine Raf/MEK/ERK cascade and recruit HSP90 as a bypass pathway. Simultaneous treatment with the HSP90 inhibitor and CY-9d at sub-therapeutic doses was found to produce synergistic therapeutic and apoptosis-inducing effects in TNBC cells. Moreover, CY-9d was also found to suppress breast cancer growth, inhibit the activation of Raf/ERK, and induce mitochondrial apoptosis in vivo without remarkable toxicity. These results support the combination of HSP90 and Raf/ERK inhibitors as a potential target therapeutic strategy with enhanced tumor growth suppression, downstream pathway blockade, and greater induction of apoptosis.
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