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.
Highlights
Lung cancer is the second most common cancer and the leading cause of cancer-related mortality among men and women worldwide[1]; its underlying mechanism remains unclear
CDK1 is a key determinant of mitotic progression, and its activity is dysregulated via indirect genetic alteration in tumorigenesis[2]
CDK1 and STAT3 are essential for iron-mediated colony formation in lung cancer cell lines
Summary
Lung cancer is the second most common cancer and the leading cause of cancer-related mortality among men and women worldwide[1]; its underlying mechanism remains unclear. A better understanding of the molecular mechanism underlying lung carcinogenesis would contribute to the development of novel strategies for its prevention and targeted therapy. Cyclin-dependent kinases (CDKs) are critical drivers of cell cycle transition. CDK1 is a key determinant of mitotic progression, and its activity is dysregulated via indirect genetic alteration in tumorigenesis[2]. Integration of gene expression data from different databases (TCGA and GEO) demonstrated CDK1 upregulation in lung adenocarcinoma. CDK1 upregulation is associated with a poor prognosis[3]. Selective targeting of CDK1 might constitute a novel strategy for tumor treatment in certain contexts. CDK1 inhibition is selectively lethal in MYC-dependent human breast cancer cells[4]. As CDK1 activity is essential for the formation of BRCA-1 foci, its inhibition, combined with
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