p16Ink4a and p21Cip1/Waf1 promote tumour growth by enhancing myeloid-derived suppressor cells chemotaxis

Atsushi Okuma (), Aki Hanyu, Sugiko Watanabe and Eiji Hara ()
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Atsushi Okuma: Research Institute for Microbial Diseases, Osaka University, 3-1 Yamadaoka
Aki Hanyu: Japanese Foundation for Cancer Research
Sugiko Watanabe: Research Institute for Microbial Diseases, Osaka University, 3-1 Yamadaoka
Eiji Hara: Research Institute for Microbial Diseases, Osaka University, 3-1 Yamadaoka

Nature Communications, 2017, vol. 8, issue 1, 1-13

Abstract: 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.

Date: 2017
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DOI: 10.1038/s41467-017-02281-x

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