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

• Published in: Cell death & disease Vol. 10; no. 4; p. 297
• Main Authors: Kuang, Yanbin, Guo, Wenzheng, Ling, Jing, Xu, Dongliang, Liao, Yueling, Zhao, Hui, Du, Xiaohui, Wang, Han, Xu, Mingxin, Song, Hongyong, Wang, Tong, Jing, Bo, Li, Kaimi, Hu, Min, Wu, Wenjuan, Deng, Jiong, Wang, Qi
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.04.2019; Springer Nature B.V
• Subjects: 13/1; 13/105; 13/109; 13/21; 13/51; 13/89; 13/95; 14/63; 45/77; 631/67/1612/1350; 631/67/2327; 64/60; A549 Cells; Adaptor Proteins, Signal Transducing - chemistry; Adaptor Proteins, Signal Transducing - metabolism; Adenocarcinoma of Lung - genetics; Adenocarcinoma of Lung - metabolism; Animals; Antibodies; Biochemistry; Biomedical and Life Sciences; Carcinogenesis; Carcinogenesis - chemistry; Carcinogenesis - drug effects; Carcinogenesis - genetics; CDC2 Protein Kinase - genetics; CDC2 Protein Kinase - metabolism; Cell Biology; Cell Culture; Cell Cycle Proteins - chemistry; Cell Cycle Proteins - metabolism; Cytokine Receptor gp130 - genetics; Cytokine Receptor gp130 - metabolism; Deferoxamine - pharmacology; Glycoprotein gp130; HEK293 Cells; Humans; Immunology; Interleukin 6; Interleukin 6 receptors; Interleukin-6 - metabolism; Iron; Iron - metabolism; Janus kinase; Janus Kinase 1 - genetics; Janus Kinase 1 - metabolism; Kinases; Life Sciences; Lung cancer; Lung diseases; Lung Neoplasms - genetics; Lung Neoplasms - metabolism; Mice; Mice, Nude; Phosphorylation; Post-transcription; Signal transduction; Signal Transduction - drug effects; Signal Transduction - genetics; Stat3 protein; STAT3 Transcription Factor - genetics; STAT3 Transcription Factor - metabolism; Tumor cell lines; Tumorigenicity
• ISSN: 2041-4889; 2041-4889
• DOI: 10.1038/s41419-019-1528-y

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.