Combined treatment of mitoxantrone sensitizes breast cancer cells to rapalogs through blocking eEF-2K-mediated activation of Akt and autophagy View Full Text


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2020-11-03

AUTHORS

Yidi Guan, Shilong Jiang, Wenling Ye, Xingcong Ren, Xinluan Wang, Yi Zhang, Mingzhu Yin, Kuansong Wang, Yongguang Tao, JinMing Yang, Dongsheng Cao, Yan Cheng

ABSTRACT

Oncogenic activation of the mTOR signaling pathway occurs frequently in tumor cells and contributes to the devastating features of cancer, including breast cancer. mTOR inhibitors rapalogs are promising anticancer agents in clinical trials; however, rapalogs resistance remains an unresolved clinical challenge. Therefore, understanding the mechanisms by which cells become resistant to rapalogs may guide the development of successful mTOR-targeted cancer therapy. In this study, we found that eEF-2K, which is overexpressed in cancer cells and is required for survival of stressed cells, was involved in the negative-feedback activation of Akt and cytoprotective autophagy induction in breast cancer cells in response to mTOR inhibitors. Therefore, disruption of eEF-2K simultaneously abrogates the two critical resistance signaling pathways, sensitizing breast cancer cells to rapalogs. Importantly, we identified mitoxantrone, an admitted anticancer drug for a wide range of tumors, as a potential inhibitor of eEF-2K via a structure-based virtual screening strategy. We further demonstrated that mitoxantrone binds to eEF-2K and inhibits its activity, and the combination treatment of mitoxantrone and mTOR inhibitor resulted in significant synergistic cytotoxicity in breast cancer. In conclusion, we report that eEF-2K contributes to the activation of resistance signaling pathways of mTOR inhibitor, suggesting a novel strategy to enhance mTOR-targeted cancer therapy through combining mitoxantrone, an eEF-2K inhibitor. More... »

PAGES

948

Journal

TITLE

Cell Death & Disease

ISSUE

11

VOLUME

11

Identifiers

URI

http://scigraph.springernature.com/pub.10.1038/s41419-020-03153-x

DOI

http://dx.doi.org/10.1038/s41419-020-03153-x

DIMENSIONS

https://app.dimensions.ai/details/publication/pub.1132263726

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/33144562


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32 schema:description Oncogenic activation of the mTOR signaling pathway occurs frequently in tumor cells and contributes to the devastating features of cancer, including breast cancer. mTOR inhibitors rapalogs are promising anticancer agents in clinical trials; however, rapalogs resistance remains an unresolved clinical challenge. Therefore, understanding the mechanisms by which cells become resistant to rapalogs may guide the development of successful mTOR-targeted cancer therapy. In this study, we found that eEF-2K, which is overexpressed in cancer cells and is required for survival of stressed cells, was involved in the negative-feedback activation of Akt and cytoprotective autophagy induction in breast cancer cells in response to mTOR inhibitors. Therefore, disruption of eEF-2K simultaneously abrogates the two critical resistance signaling pathways, sensitizing breast cancer cells to rapalogs. Importantly, we identified mitoxantrone, an admitted anticancer drug for a wide range of tumors, as a potential inhibitor of eEF-2K via a structure-based virtual screening strategy. We further demonstrated that mitoxantrone binds to eEF-2K and inhibits its activity, and the combination treatment of mitoxantrone and mTOR inhibitor resulted in significant synergistic cytotoxicity in breast cancer. In conclusion, we report that eEF-2K contributes to the activation of resistance signaling pathways of mTOR inhibitor, suggesting a novel strategy to enhance mTOR-targeted cancer therapy through combining mitoxantrone, an eEF-2K inhibitor.
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38 schema:keywords Akt
39 Combined treatment
40 EEF
41 K inhibitors
42 activation
43 activation of Akt
44 activation of resistance
45 activity
46 agents
47 anticancer agents
48 anticancer drugs
49 breast cancer
50 breast cancer cells
51 cancer
52 cancer cells
53 cancer therapy
54 cells
55 challenges
56 clinical challenge
57 clinical trials
58 combination treatment
59 conclusion
60 critical resistance
61 cytotoxicity
62 devastating features
63 development
64 disruption
65 drugs
66 eEF-2K
67 eEF-2K inhibitor
68 features
69 induction
70 inhibitors
71 mTOR
72 mTOR inhibitors
73 mechanism
74 mitoxantrone
75 negative feedback activation
76 novel strategy
77 oncogenic activation
78 pathway
79 potential inhibitors
80 range
81 rapalog resistance
82 rapalogs
83 resistance
84 response
85 screening strategy
86 significant synergistic cytotoxicity
87 strategies
88 structure-based virtual screening strategy
89 study
90 survival
91 synergistic cytotoxicity
92 therapy
93 treatment
94 trials
95 tumor cells
96 tumors
97 unresolved clinical challenge
98 virtual screening strategy
99 wide range
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