Abstract
p16Ink4a 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 p16 Ink4 and p21 Cip1/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 p16 Ink4a and p21 Waf1/Cip1 and indicate that regulation of Mo-MDSCs chemotaxis is a valuable potential strategy for control of tumour development.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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CX3C Chemokine Receptor 1 / antagonists & inhibitors
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CX3C Chemokine Receptor 1 / metabolism
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Chemotaxis*
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Cyclin-Dependent Kinase Inhibitor p16 / genetics
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Cyclin-Dependent Kinase Inhibitor p16 / metabolism*
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Cyclin-Dependent Kinase Inhibitor p21 / genetics
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Cyclin-Dependent Kinase Inhibitor p21 / metabolism*
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Cyclin-Dependent Kinases / antagonists & inhibitors
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Cyclin-Dependent Kinases / metabolism
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Dimethyl Sulfoxide / pharmacology
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Disease Progression
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Female
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Flavonoids / pharmacology
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Humans
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Male
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Myeloid-Derived Suppressor Cells / pathology*
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Neoplasms / pathology*
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Phosphorylation
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Piperidines / pharmacology
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Smad3 Protein / metabolism
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Up-Regulation
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Xenograft Model Antitumor Assays
Substances
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CX3C Chemokine Receptor 1
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Cdkn1a protein, mouse
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Cdkn2a protein, mouse
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Cx3cr1 protein, mouse
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Cyclin-Dependent Kinase Inhibitor p16
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Cyclin-Dependent Kinase Inhibitor p21
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Flavonoids
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Piperidines
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Smad3 Protein
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Smad3 protein, mouse
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alvocidib
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Cyclin-Dependent Kinases
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Dimethyl Sulfoxide