Back to Search
Start Over
Inhibitory Effect of Tumor Suppressor p53 on Proinflammatory Chemokine Expression in Ovarian Cancer Cells by Reducing Proteasomal Degradation of IκB
- Source :
- PLoS ONE, Vol 7, Iss 12, p e51116 (2012), PLoS ONE
- Publication Year :
- 2012
- Publisher :
- Public Library of Science (PLoS), 2012.
-
Abstract
- Ovarian cancer, one of inflammation-associated cancers, is the fifth leading cause of cancer deaths among women. Inflammation in the tumor microenvironment is associated with peritoneal tumor dissemination and massive ascites, which contribute to high mortality in ovarian cancer. Tumor suppressor p53 is frequently deleted or mutated in aggressive and high-grade ovarian cancer, probably aggravating cancer progression and increasing mortality. We therefore investigated the influence of p53 on proinflammatory chemokines in ovarian cancer cells. A PCR array of the chemokine network revealed that ovarian cancer cells with low or mutated p53 expression expressed high levels of proinflammatory chemokines such as CXCL1, 2, 3 and 8. Transient transfection of p53 into p53-null ovarian cancer cells downregulated proinflammatory chemokines induced by tumor necrosis factor-α (TNF), a proinflammatory cytokine abundantly expressed in ovarian cancer. Furthermore, p53 restoration or stabilization blocked TNF-induced NF-κB promoter activity and reduced TNF-activated IκB. Restoration of p53 increased ubiquitination of IκB, resulting from concurrently reduced proteasome activity followed by stability of IκB. A ubiquitination PCR array on restoration of p53 did not reveal any significant change in expression except for Mdm2, indicating that the balance between p53 and Mdm2 is more important in regulating NF-κB signaling rather than the direct effect of p53 on ubiquitin-related genes or IκB kinases. In addition, nutlin-3, a specific inducer of p53 stabilization, inhibited proinflammatory chemokines by reducing TNF-activated IκB through p53 stabilization. Taken together, these results suggest that p53 inhibits proinflammatory chemokines in ovarian cancer cells by reducing proteasomal degradation of IκB. Thus, frequent loss or mutation of p53 may promote tumor progression by enhancing inflammation in the tumor microenvironment.
- Subjects :
- Tumor Physiology
lcsh:Medicine
0302 clinical medicine
Molecular Cell Biology
Basic Cancer Research
Tumor Cells, Cultured
Promoter Regions, Genetic
lcsh:Science
Ovarian Neoplasms
0303 health sciences
Multidisciplinary
Cancer Risk Factors
NF-kappa B
Proto-Oncogene Proteins c-mdm2
Signaling in Selected Disciplines
Ovarian Cancer
I-kappa B Kinase
3. Good health
CXCL1
Oncology
030220 oncology & carcinogenesis
Cytokines
Medicine
Mdm2
Female
Tumor necrosis factor alpha
Chemokines
Inflammation Mediators
Research Article
Signal Transduction
Proteasome Endopeptidase Complex
Immunology
Genetic Causes of Cancer
Biology
Immunological Signaling
Proinflammatory cytokine
03 medical and health sciences
medicine
Humans
030304 developmental biology
Oncogenic Signaling
Tumor microenvironment
Tumor Necrosis Factor-alpha
lcsh:R
Ubiquitination
Cancers and Neoplasms
Cancer
medicine.disease
Tumor progression
Immune System
Proteolysis
Cancer research
biology.protein
lcsh:Q
Tumor Suppressor Protein p53
Ovarian cancer
Gynecological Tumors
Subjects
Details
- ISSN :
- 19326203
- Volume :
- 7
- Database :
- OpenAIRE
- Journal :
- PLoS ONE
- Accession number :
- edsair.doi.dedup.....23dc30fc58c499d0afd367b7eba1c1d3