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Cited by 33Immune cells in cancerCell death mechanisms and regulationPhagocytosis and Immune Regulation

Downregulation of programmed cell death 4 by inflammatory conditions contributes to the generation of the tumor promoting microenvironment

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Yasuda, Michiko, Schmid, Tobias, Rübsamen, Daniela, Colburn, Nancy H., Irie, Kazuhiro, Murakami, Akira·2010·Molecular Carcinogenesis
DOI 10.1002/mc.20660PMC PMC3472367
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Abstract

Ample evidence has shown key roles of inflammation in tumor promotion and carcinogenesis, and tumor‐associated macrophages are known to promote tumor growth and dissemination. Programmed cell death 4 (Pdcd4) is a novel tumor suppressor, and although various studies have revealed that the functions and expression mechanisms of Pdcd4 in tumor promotion, those in regard to inflammation remain unclear. In the present study, we examined whether inflammatory stimuli regulate Pdcd4 expression. 12‐ O ‐tetradecanoylphorbol 13‐acetate (TPA) suppressed expression of pdcd4 mRNA in human monocytic cell lines (U937, THP‐1). Similarly, the bacterial endotoxin lipopolysaccharide (LPS) downregulated pdcd4 level in mouse RAW264.7 and peritoneal macrophages. Furthermore, conditioned medium from LPS‐stimulated RAW264.7 macrophages suppressed pdcd4 mRNA in RAW264.7 macrophages, and findings obtained with recombinant tumor necrosis factor‐α (TNF‐α) and TNF‐α‐specific siRNA suggested that TNF‐α partly mediates LPS‐triggered Pdcd4 downregulation via an autocrine mechanism. Specific inhibitors of phosphoinositide‐3‐kinase (PI3K) and c‐ jun N ‐terminus kinase (JNK) restored LPS‐abolished pdcd4 mRNA. Consistently, in MCF7 mammary carcinoma cells, conditioned medium from TPA‐differentiated/activated U937 cells suppressed pdcd4 mRNA. Additionally, knockdown of pdcd4 in RAW264.7 macrophages using siRNA significantly enhanced LPS‐induced TNF‐α protein production, and interferon ‐γ, CC chemokine ligand ( Ccl ) 1, Ccl20 , and interleukin‐10 mRNA expression. These results suggest that Pdcd4 suppresses the induction of these inflammatory mediators. Taken together, loss of Pdcd4 in macrophages may be a critical step in establishing the inflammatory environment while that in tumor cells contributes to tumor progression. © 2010 Wiley‐Liss, Inc.

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  • Conditional medium of activated macrophages downregulated PDCD4 protein levels, activating the PI3K-Akt-mTOR-S6K signaling pathway and phosphorylating PDCD4 protein in various tumor cells.

    “The conditional medium of the activated macrophages downregulated PDCD4-protein levels, activating the PI3K-Akt-mTOR-S6K signaling pathway and phosphorylating PDCD4-protein in various tumor cells [74,75].”

    From Control Mechanisms of the Tumor Suppressor PDCD4: Expression and Functions (2019) · cites this paper as [75]

    The Results section, “Inflammatory Macrophages Limit pdcd4 mRNA Expression in Tumor Cells” (page unavailable), reports that conditioned medium from activated U937 cells reduced pdcd4 mRNA in MCF7 tumor cells. It does not establish reduced PDCD4 protein in various tumor cells or PDCD4 phosphorylation. The same section says PI3K inhibition did not reverse the conditioned-medium effect in MCF7 cells; the paper links PI3K to LPS responses in macrophages, not to the claimed PI3K–Akt–mTOR–S6K mechanism in tumor cells. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • PDCD4 suppression induces expression of IL-10 and TNFα.

    “PDCD4 suppression then induces the expression of IL-10 and TNFα [21,74,75].”

    From Control Mechanisms of the Tumor Suppressor PDCD4: Expression and Functions (2019) · cites this paper as [75]

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Authors
Yasuda, M., Schmid, T., Rübsamen, D., Colburn, N. H., Irie, K., & Murakami, A.
Affiliations
  • Kyoto University (JP)
  • Goethe University Frankfurt (DE)
  • Frederick National Laboratory for Cancer Research (US)
Corresponding author
Murakami, Akira
ORCID
Venue
Molecular Carcinogenesis
Publisher
Wiley
Published
2010-08-05
Volume
49
Issue
9
Pages
837-848
ISSN
  • 0899-1987 (ISSN-L)
  • 1098-2744
DOI
10.1002/mc.20660
PMC
PMC3472367
OpenAlex
W1977156161
Cited by
33
References
4
Citations by year
2026: 1 · 2024: 1 · 2021: 2 · 2020: 4 · 2019: 2 · 2018: 2 · 2017: 1 · 2016: 2 · 2015: 2 · 2014: 6 · 2013: 4 · 2012: 2
FWCI
1.38
Type
journal article
Language
en
Open access
Licence
onlinelibrary.wiley.com/termsAndConditions#vor (vor)
Locations
  • Molecular Carcinogenesis (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • National Institutes of Health
  • National Cancer Institute (ZIABC010026)
Topics
  • Life Sciences › Immunology and Microbiology › Immunology › Immune cells in cancer
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
  • Life Sciences › Immunology and Microbiology › Immunology › Phagocytosis and Immune Regulation
Keywords
PDCD4, tumor microenvironment, inflammation, tumor-associated macrophages, lipopolysaccharide, TNF-α, autocrine signaling, phosphatidylinositol 3-kinase, JNK, tumor suppressor, macrophage polarization, interferon-gamma, CCL1, CCL20, IL-10, tumor progression
MeSH terms
Animals, Carcinogens, Cell Line, Female, Humans, Interferon-gamma, Lipopolysaccharides, Macrophages, Mice, Inbred ICR, Monocytes, Recombinant Proteins, RNA, Messenger, Tumor Necrosis Factor-alpha, Down-Regulation, Interleukin-10, Apoptosis, Macrophages, Peritoneal, U937 Cells, RNA, Small Interfering, Mice

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