p16Ink4a and p21Cip1/Waf1 promote tumour growth by enhancing myeloid-derived suppressor cells chemotaxis
Open accessAbstract
p16 Ink4a and p21 Cip1/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 p16 Ink4 and p21 Cip1/Waf1, namely, tumour promotion through chemotaxis. In monocytic myeloid-derived suppressor cells (Mo-MDSCs), p16 Ink4 and p21 Cip1/Waf1 are highly expressed and stimulate CX3CR1 chemokine receptor expression by preventing CDK-mediated phosphorylation and inactivation of SMAD3. Thus, deletion of p16Ink4and p21Cip1/Waf1reduces 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 p16Ink4aand p21Waf1/Cip1and indicate that regulation of Mo-MDSCs chemotaxis is a valuable potential strategy for control of tumour development.
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Some macrophages and myeloid-derived suppressor cells also express p16 in response to physiological stimuli regardless of aging.
“Interestingly, some macrophage [15] and myeloid-derived suppressor cells (MDSCs) also express p16 in response to physiological stimuli regardless of aging [16].”
From The role of cellular senescence and SASP in tumour microenvironment (2023) · cites this paper as [16]
The Results section ('p16 and p21 are expressed in MDSCs in tumour-bearing mice'; page unavailable) reports p16 expression in MDSCs and finds that these cells are unlikely to be senescent. The experiments concern tumour-bearing mice, however, and do not establish that physiological stimuli induce p16 expression regardless of aging. The macrophage claim is attached to a different citation and is not assessed here. (LLM, conf=0.86)
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References 72 · Cited by 69
- Authors
- Okuma, A., Hanyu, A., Watanabe, S., & Hara, E.
- Affiliations
- Japanese Foundation For Cancer Research (JP)
- Research Institute for Microbial Diseases, The University of Osaka (JP)
- Corresponding author
- Okuma, Atsushi
- Hara, Eiji
- Venue
- Nature Communications
- Published
- 2017-12-12
- Volume
- 8
- Issue
- 1
- Pages
- 2050-2050
- ISSN
- 2041-1723 (ISSN-L)
- PMC
- PMC5727112
- OpenAlex
- W2775087955
- Cited by
- 69
- References
- 72
- Citations by year
- 2026: 4 · 2025: 11 · 2024: 8 · 2023: 10 · 2022: 10 · 2021: 4 · 2020: 8 · 2019: 13 · 2018: 1
- FWCI
- 2.72
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Nature Communications (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- Funders
- Japan Agency for Medical Research and Development
- Jikei University School of Medicine
- Japan Society for the Promotion of Science (14J10280, 26250028, 16K19064)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Immune cells in cancer
- Health Sciences › Medicine › Oncology › Chemokine receptors and signaling
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Keywords
- p16INK4a, p21, myeloid-derived suppressor cells, cyclin-dependent kinase inhibitors, Smad3 phosphorylation, monocytic MDSCs, tumor growth, tumor immunosuppression
- MeSH terms
- Myeloid-Derived Suppressor Cells, CX3C Chemokine Receptor 1, Animals, Chemotaxis, Dimethyl Sulfoxide, Female, Flavonoids, Humans, Male, Mice, Inbred C57BL, Neoplasms, Phosphorylation, Piperidines, Up-Regulation, Mice, Knockout, Disease Progression, Cyclin-Dependent Kinases, Cyclin-Dependent Kinase Inhibitor p16, Xenograft Model Antitumor Assays, Cyclin-Dependent Kinase Inhibitor p21, Mice, Smad3 Protein
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