Reference - Detail
| RRC ID | 52518 |
|---|---|
| Author | Okuma A, Hanyu A, Watanabe S, Hara E. |
| Title | p16Ink4a and p21Cip1/Waf1 promote tumour growth by enhancing myeloid-derived suppressor cells chemotaxis. |
| Journal | Nat Commun |
| 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. |
| Volume | 8(1) |
| Pages | 2050 |
| Published | 2017-12-12 |
| DOI | 10.1038/s41467-017-02281-x |
| PII | 10.1038/s41467-017-02281-x |
| PMID | 29234059 |
| PMC | PMC5727112 |
| MeSH | Animals CX3C Chemokine Receptor 1 / antagonists & inhibitors CX3C Chemokine Receptor 1 / metabolism Chemotaxis* Cyclin-Dependent Kinase Inhibitor p16 / genetics Cyclin-Dependent Kinase Inhibitor p16 / metabolism* Cyclin-Dependent Kinase Inhibitor p21 / genetics Cyclin-Dependent Kinase Inhibitor p21 / metabolism* 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 Myeloid-Derived Suppressor Cells / pathology* Neoplasms / pathology* Phosphorylation Piperidines / pharmacology Smad3 Protein / metabolism Up-Regulation Xenograft Model Antitumor Assays |
| IF | 12.121 |
| Times Cited | 16 |
| Resource | |
| Human and Animal Cells | LLC(RCB0558) |