IL-6 regulates autophagy and chemotherapy resistance by promoting BECN1 phosphorylation

Fuqing Hu, Da Song, Yumeng Yan, Changsheng Huang, Chentao Shen, Jingqin Lan, Yaqi Chen, Anyi Liu, Qi Wu, Li Sun, Feng Xu, Fayong Hu, Lisheng Chen, Xuelai Luo, Yongdong Feng, Shengyou Huang, Junbo Hu () and Guihua Wang ()
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Fuqing Hu: GI Cancer Research Institute, Tongji Hospital, Huazhong University of Science and Technology
Da Song: GI Cancer Research Institute, Tongji Hospital, Huazhong University of Science and Technology
Yumeng Yan: School of Physics, Huazhong University of Science and Technology
Changsheng Huang: GI Cancer Research Institute, Tongji Hospital, Huazhong University of Science and Technology
Chentao Shen: GI Cancer Research Institute, Tongji Hospital, Huazhong University of Science and Technology
Jingqin Lan: GI Cancer Research Institute, Tongji Hospital, Huazhong University of Science and Technology
Yaqi Chen: GI Cancer Research Institute, Tongji Hospital, Huazhong University of Science and Technology
Anyi Liu: GI Cancer Research Institute, Tongji Hospital, Huazhong University of Science and Technology
Qi Wu: GI Cancer Research Institute, Tongji Hospital, Huazhong University of Science and Technology
Li Sun: Tongji Hospital, Huazhong University of Science and Technology
Feng Xu: GI Cancer Research Institute, Tongji Hospital, Huazhong University of Science and Technology
Fayong Hu: GI Cancer Research Institute, Tongji Hospital, Huazhong University of Science and Technology
Lisheng Chen: GI Cancer Research Institute, Tongji Hospital, Huazhong University of Science and Technology
Xuelai Luo: GI Cancer Research Institute, Tongji Hospital, Huazhong University of Science and Technology
Yongdong Feng: GI Cancer Research Institute, Tongji Hospital, Huazhong University of Science and Technology
Shengyou Huang: School of Physics, Huazhong University of Science and Technology
Junbo Hu: GI Cancer Research Institute, Tongji Hospital, Huazhong University of Science and Technology
Guihua Wang: GI Cancer Research Institute, Tongji Hospital, Huazhong University of Science and Technology

Nature Communications, 2021, vol. 12, issue 1, 1-14

Abstract: Abstract Extracellular cytokines are enriched in the tumor microenvironment and regulate various important properties of cancers, including autophagy. However, the precise molecular mechanisms underlying the link between autophagy and extracellular cytokines remain to be elucidated. In the present study, we demonstrate that IL-6 activates autophagy through the IL-6/JAK2/BECN1 pathway and promotes chemotherapy resistance in colorectal cancer (CRC). Mechanistically, IL-6 triggers the interaction between JAK2 and BECN1, where JAK2 phosphorylates BECN1 at Y333. We demonstrate that BECN1 Y333 phosphorylation is crucial for BECN1 activation and IL-6-induced autophagy by regulating PI3KC3 complex formation. Furthermore, we investigate BECN1 Y333 phosphorylation as a predictive marker for poor CRC prognosis and chemotherapy resistance. Combination treatment with autophagy inhibitors or pharmacological agents targeting the IL-6/JAK2/BECN1 signaling pathway may represent a potential strategy for CRC cancer therapy.

Date: 2021
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DOI: 10.1038/s41467-021-23923-1

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