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Plos One : Inhibitory Effect of Tumor Suppressor P53 on Proinflammatory Chemokine Expression in Ovarian Cancer Cells by Reducing Proteasomal Degradation of Ikb, Volume 7

By Kumar, Ashok

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Book Id: WPLBN0003939598
Format Type: PDF eBook :
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Reproduction Date: 2015

Title: Plos One : Inhibitory Effect of Tumor Suppressor P53 on Proinflammatory Chemokine Expression in Ovarian Cancer Cells by Reducing Proteasomal Degradation of Ikb, Volume 7  
Author: Kumar, Ashok
Volume: Volume 7
Language: English
Subject: Journals, Science, Medical Science
Collection: Periodicals: Journal and Magazine Collection (Contemporary)
Publication Date:
Publisher: Plos

Description : 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-a (TNF), a proinflammatory cytokine abundantly expressed in ovarian cancer. Furthermore, p53 restoration or stabilization blocked TNF-induced NF-kB promoter activity and reduced TNF-activated IkB. Restoration of p53 increased ubiquitination of IkB, resulting from concurrently reduced proteasome activity followed by stability of IkB. 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-kB signaling rather than the direct effect of p53 on ubiquitin-related genes or IkB kinases. In addition, nutlin-3, a specific inducer of p53 stabilization, inhibited proinflammatory chemokines by reducing TNF-activated IkB through p53 stabilization. Taken together, these results suggest that p53 inhibits proinflammatory chemokines in ovarian cancer cells by reducing proteasomal degradation of IkB. Thus, frequent loss or mutation of p53 may promote tumor progression by enhancing inflammation in the tumor microenvironment.


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