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

Author

Listed:
  • Atsushi Okuma

    (Research Institute for Microbial Diseases, Osaka University, 3-1 Yamadaoka
    Japanese Foundation for Cancer Research)

  • 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
    Japanese Foundation for Cancer Research)

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.

Suggested Citation

  • Atsushi Okuma & Aki Hanyu & Sugiko Watanabe & Eiji Hara, 2017. "p16Ink4a and p21Cip1/Waf1 promote tumour growth by enhancing myeloid-derived suppressor cells chemotaxis," Nature Communications, Nature, vol. 8(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:8:y:2017:i:1:d:10.1038_s41467-017-02281-x
    DOI: 10.1038/s41467-017-02281-x
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