1. p16 Ink4a and p21 Cip1/Waf1 promote tumour growth by enhancing myeloid-derived suppressor cells chemotaxis.
- Author
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Okuma A, Hanyu A, Watanabe S, and Hara E
- Subjects
- Animals, CX3C Chemokine Receptor 1 antagonists & inhibitors, CX3C Chemokine Receptor 1 metabolism, Cyclin-Dependent Kinase Inhibitor p16 genetics, Cyclin-Dependent Kinase Inhibitor p21 genetics, Cyclin-Dependent Kinases antagonists & inhibitors, Cyclin-Dependent Kinases metabolism, Dimethyl Sulfoxide pharmacology, Disease Progression, Female, Flavonoids pharmacology, Humans, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Phosphorylation, Piperidines pharmacology, Smad3 Protein metabolism, Up-Regulation, Xenograft Model Antitumor Assays, Chemotaxis, Cyclin-Dependent Kinase Inhibitor p16 metabolism, Cyclin-Dependent Kinase Inhibitor p21 metabolism, Myeloid-Derived Suppressor Cells pathology, Neoplasms pathology
- Abstract
p16
Ink4a and p21Cip1/Waf1 act as tumour suppressors through induction of cellular senescence. However, senescence-independent roles of these CDK inhibitors are not well understood. Here, we report an unexpected function of p16Ink4 and p21Cip1/Waf1 , namely, tumour promotion through chemotaxis. In monocytic myeloid-derived suppressor cells (Mo-MDSCs), p16Ink4 and p21Cip1/Waf1 are highly expressed and stimulate CX3CR1 chemokine receptor expression by preventing CDK-mediated phosphorylation and inactivation of SMAD3. Thus, deletion of p16Ink4 and p21Cip1/Waf1 reduces CX3CR1 expression, thereby inhibiting Mo-MDSC accumulation in tumours expressing CX3CL1 and suppressing the tumour progression in mice. Notably, blockade of the CX3CL1/CX3CR1 axis suppresses tumour growth, whereas inactivation of CDKs elicits the opposite effect. These findings reveal an unexpected function of p16Ink4a and p21Waf1/Cip1 and indicate that regulation of Mo-MDSCs chemotaxis is a valuable potential strategy for control of tumour development.- Published
- 2017
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