Autophagy inhibition by sustained overproduction of IL6 contributes to arsenic carcinogenesis.
Chronic inflammation has been implicated as an etiologic factor in cancer, whereas autophagy may help preserve cancer cell survival but exert anti-inflammatory effects. How these phenomenas interact during carcinogenesis remains unclear. We explored this question in a human bronchial epithelial cell-based model of lung carcinogenesis that is mediated by subchronic exposure to arsenic. We found that sustained overexpression of the pro-inflammatory IL6 promoted arsenic-induced cell transformation by inhibiting autophagy. Conversely, strategies to enhance autophagy counteracted the effect of IL6 in the model. These findings were confirmed and extended in a mouse model of arsenic-induced lung cancer. Mechanistic investigations suggested that mTOR inhibition contributed to the activation of autophagy, whereas IL6 overexpression was sufficient to block autophagy by supporting Beclin-1/Mcl-1 interaction. Overall, our findings argued that chronic inflammatory states driven by IL6 could antagonize autophagic states that may help preserve cancer cell survival and promote malignant progression, suggesting a need to uncouple inflammation and autophagy controls to enable tumor progression.
Authors' Affiliations: Department of Molecular & Biomedical Pharmacology, Biochemistry and Molecular Biology and.
Yuanlin
Y
Qi
Authors' Affiliations: Department of Molecular & Biomedical Pharmacology, Physiology and Pathophysiology, School of Basic Medical Sciences, Fujian Medical University, Fuzhou, Fujian, China.
Mingfang
M
Zhang
Authors' Affiliations: Department of Molecular & Biomedical Pharmacology.
Hui
H
Li
Authors' Affiliations: Department of Molecular & Biomedical Pharmacology.
Jacqueline A
JA
Frank
Graduate Center for Toxicology, University of Kentucky College of Medicine;
Lu
L
Dai
Authors' Affiliations: Department of Molecular & Biomedical Pharmacology.
Huijuan
H
Liu
Graduate Center for Toxicology, University of Kentucky College of Medicine;
Zhuo
Z
Zhang
Biostatistics Shared Resource Facility, Markey Cancer Center and Department of Biostatistics, University of Kentucky College of Public Health, Lexington, Kentucky; and Departments of.
Chi
C
Wang
Authors' Affiliations: Department of Molecular & Biomedical Pharmacology, gangchen6@uky.edu.
Gang
G
Chen
D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D001151:Arsenic / Q000494:pharmacology*; D001343:Autophagy / Q000187:drug effects* / Q000235:genetics; D000071186:Beclin-1; D002460:Cell Line; D002471:Cell Transformation, Neoplastic / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism*; D004847:Epithelial Cells / Q000378:metabolism; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000096:biosynthesis / Q000235:genetics; D006801:Humans; D015850:Interleukin-6 / Q000096:biosynthesis* / Q000235:genetics; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000378:metabolism; D011485:Protein Binding; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism
D051017:Apoptosis Regulatory Proteins; C491997:BECN1 protein, human; D000071186:Beclin-1; D015850:Interleukin-6; D008565:Membrane Proteins; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D012333:RNA, Messenger; D050796:STAT3 Transcription Factor; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D058570:TOR Serine-Threonine Kinases; D001151:Arsenic