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Cell Death Dis. 2019 Apr 1;10(4):297. doi: 10.1038/s41419-019-1528-y.

Iron-dependent CDK1 activity promotes lung carcinogenesis via activation of the GP130/STAT3 signaling pathway.

Author information

1
Department of Respiratory Medicine, The Second Affiliated Hospital, Dalian Medical University, Dalian, China.
2
Key Laboratory of Cell Differentiation and Apoptosis of Chinese Minister of Education, Shanghai, China.
3
Department of Laboratory Medicine, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China.
4
Department of Oncology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
5
Department of Health Examination Center, The Second Affiliated Hospital, Dalian Medical University, Dalian, China.
6
Department of Scientific Research Center, The Second Affiliated Hospital, Dalian Medical University, Dalian, China.
7
Department of Pharmacy, The Second Affiliated Hospital, Dalian Medical University, Dalian, China.
8
Key Laboratory of Cell Differentiation and Apoptosis of Chinese Minister of Education, Shanghai, China. jiongdeng@shsmu.edu.cn.
9
Department of Respiratory Medicine, The Second Affiliated Hospital, Dalian Medical University, Dalian, China. wqdlmu@163.com.

Abstract

Iron dysregulation is associated with several diseases, including lung cancer, but the underlying mechanism is yet unknown. Iron directly binds CDK1, which is upregulated in several cancers, thereby promoting JAK1 phosphorylation and activation of STAT3 signaling to promote colorectal carcinogenesis. This study aimed to investigate the role of iron/CDK1/STAT3 signaling in lung carcinogenesis. We found that iron-dependent CDK1 activity upregulated IL-6 receptor subunit GP130 post-transcriptionally via phosphorylation of 4E-BP1, which is critical for activation of JAK/STAT3 signaling. CDK1 and STAT3 are essential for iron-mediated colony formation in lung cancer cell lines. CDK1 knockdown and iron chelator DFO decreased tumorigenicity and GP130/STAT3 signaling in vivo. Moreover, CDK1/GP130/STAT3 signaling were elevated in lung cancer tissues compared with adjacent normal lung tissues. Altogether, the present results suggest that CDK1 inhibition and iron deprivation are potential strategies to target GP130/STAT3 signaling to suppress lung cancer.

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