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

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.

• Authors: 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, Guihua Wang
• Journal: Nature communications (Nat Commun) Vol. 12 Issue 1 Pg. 3651 (06 15 2021) ISSN: 2041-1723 [Electronic] England
• PMID: 34131122 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Autophagy-Related Proteins
• BECN1 protein, human
• Beclin-1
• Interleukin-6
• STAT3 Transcription Factor
• STAT3 protein, human
• JAK2 protein, human
• Janus Kinase 2

Topics

• Autophagy (drug effects, physiology)
• Autophagy-Related Proteins (metabolism)
• Beclin-1 (chemistry, genetics, metabolism)
• Cell Line, Tumor
• Colorectal Neoplasms (drug therapy, metabolism)
• Drug Resistance, Neoplasm (genetics)
• Drug Therapy
• Gene Expression Regulation, Neoplastic
• Humans
• Interleukin-6 (metabolism, pharmacology)
• Janus Kinase 2 (chemistry, metabolism)
• Phosphorylation
• Protein Interaction Domains and Motifs
• STAT3 Transcription Factor (metabolism)
• Signal Transduction (drug effects)