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p38MAPK Plays a Crucial Role in Stromal-Mediated Tumorigenesis
Open accessPublished version of a preprint
Abstract
Neoplastic cells rely on the tumor microenvironment (TME) for survival and progression factors. Indeed, senescent and cancer-associated fibroblasts (CAF) express factors that promote tumorigenesis that are collectively referred to as the senescence-associated secretory phenotype (SASP). Despite their importance in tumorigenesis, the mechanisms that control TME-derived factor expression remain poorly understood. Here, we address a key unanswered question: how the SASP is sustained in senescent fibroblasts and CAFs. We find that the mitogen-activated protein kinase p38 (p38MAPK) controls AUF1 occupancy on SASP mRNAs and thus controls their stability. The importance of this regulatory mechanism is underscored by our findings that stromal-specific p38MAPK inhibition abrogates the tumor-promoting activities of CAFs and senescent fibroblasts. Our data suggest that targeting SASP mRNA stability through inhibition of p38MAPK will significantly aid the development of clinical strategies to target the TME. Significance: The TME plays a key role in tumorigenesis. We demonstrate that p38MAPK governs a posttranscriptional mechanism that sustains the protumorigenic SASP. Inhibition of p38MAPK abrogates the tumor-promoting activities of CAFs and senescent fibroblasts. Thus, p38MAPK is a TME-specific Achilles' heel that may be exploited as a new therapeutic target. Cancer Discov; 4(6); 716–29. ©2014 AACR. See related commentary by Isacke and Barcellos-Hoff, p. 637 This article is highlighted in the In This Issue feature, p. 621
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Metadata
- Authors
- Alspach, E., Flanagan, K. C., Luo, X., Ruhland, M. K., Huang, H., Pazolli, E., Donlin, M. J., Marsh, T., Piwnica-Worms, D., Monahan, J., Novack, D. V., McAllister, S. S., & Stewart, S. A.
- Affiliations
- Broad Institute (US)
- Corresponding author
- Stewart, Sheila A.
- ORCID
- Venue
- Cancer Discovery
- Published
- 2014-06-01
- Volume
- 4
- Issue
- 6
- Pages
- 716-729
- ISSN
- 2159-8274 (ISSN-L)
- 2159-8290
- PMC
- PMC4049323
- OpenAlex
- W2121507786
- Cited by
- 167
- References
- 46
- Citations by year
- 2026: 6 · 2025: 16 · 2024: 22 · 2023: 15 · 2022: 15 · 2021: 19 · 2020: 17 · 2019: 7 · 2018: 12 · 2017: 12 · 2016: 14 · 2015: 8 · 2014: 4
- FWCI
- 8.42
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Cancer Discovery (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- American Association for Cancer Research
- Deutsches Krebsforschungszentrum
- Broad Institute
- National Cancer Institute (P50 CA94056, R01CA166284, P50CA094056, R01CA130919, T32CA113275, P30CA091842)
- National Institute of General Medical Sciences (T32GM007067)
- National Institute of Arthritis and Musculoskeletal and Skin Diseases (P30AR057235)
- National Center for Research Resources (UL1RR024992)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Telomeres, Telomerase, and Senescence
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › TGF-β signaling in diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Research and Splicing
- Keywords
- p38 MAPK, senescence-associated secretory phenotype, cancer-associated fibroblasts, senescent fibroblasts, tumor microenvironment, stromal cells, mRNA stability, AUF1, post-transcriptional regulation, carcinogenesis, therapeutic target
- MeSH terms
- Heterogeneous Nuclear Ribonucleoprotein D0, Animals, Cell Line, Cells, Cultured, Female, Fibroblasts, Humans, Imidazoles, Lipopolysaccharides, Mice, Nude, Neoplasms, Pyridines, Tumor Necrosis Factor-alpha, Cellular Senescence, Heterogeneous-Nuclear Ribonucleoprotein D, Protein Kinase Inhibitors, p38 Mitogen-Activated Protein Kinases, Tumor Microenvironment
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