Inhibitory effect of tumor suppressor p53 on proinflammatory chemokine expression in ovarian cancer cells by reducing proteasomal degradation of IκB.
Inhibitory effect of tumor suppressor p53 on proinflammatory chemokine expression in ovarian cancer cells by reducing proteasomal degradation of IκB.
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DOI：
10.1371/journal.pone.0051116
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Adunyah SE
中科院分区：
文献类型：
--
作者：
Son DS;Kabir SM;Dong YL;Lee E;Adunyah SE
卵巢癌是一种与炎症相关的癌症，是妇女癌症死亡的第五大原因。肿瘤微环境中的炎症与腹膜肿瘤扩散和大量腹水相关，这导致卵巢癌的高死亡率。肿瘤抑制因子p53在侵袭性和高级别卵巢癌中经常缺失或突变，可能加重癌症进展并增加死亡率。因此，我们研究了p53对卵巢癌细胞中促炎趋化因子的影响。趋化因子网络的PCR阵列显示，具有低或突变的p53表达的卵巢癌细胞表达高水平的促炎性趋化因子，如CXCL 1、2、3和8。瞬时转染p53到p53缺失的卵巢癌细胞下调肿瘤坏死因子-α（TNF）诱导的促炎趋化因子，TNF是一种在卵巢癌中大量表达的促炎细胞因子。此外，p53的恢复或稳定阻断了TNF诱导的NF-κB启动子活性，并降低了TNF激活的IκB。p53的恢复增加了IκB的泛素化，这是由于同时降低了蛋白酶体活性和IκB的稳定性。泛素化PCR阵列显示，p53的恢复没有显示出任何显着的变化，除了Mdm 2，表明p53和Mdm 2之间的平衡是更重要的调节NF-κB信号转导，而不是p53对泛素相关基因或IκB激酶的直接影响。此外，nutlin-3，一种p53稳定化的特异性诱导剂，通过p53稳定化减少TNF激活的IκB，抑制促炎趋化因子。综上所述，这些结果表明p53通过减少IκB的蛋白酶体降解来抑制卵巢癌细胞中的促炎趋化因子。因此，p53的频繁丢失或突变可能通过增强肿瘤微环境中的炎症来促进肿瘤进展。
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.
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DOI：
10.1034/j.1600-0412.2000.079009777.x
发表时间：
2000-09-01
影响因子：
4.3
作者：
Ivarsson, K;Ekerydh, A;Brännström, M
通讯作者：
Brännström, M
DOI：
10.1006/bbrc.2000.2786
发表时间：
2000-06-07
影响因子：
3.1
作者：
Ikeda, A;Sun, XG;Yamamoto, K
通讯作者：
Yamamoto, K
影响因子：
8
作者：
Schneider, G.;Henrich, A.;Kraemer, O. H.
通讯作者：
Kraemer, O. H.
影响因子：
20.3
作者：
Gu, LB;Findley, HW;Zhou, MX
通讯作者：
Zhou, MX
影响因子：
4.7
作者：
Roby, KF;Taylor, CC;Terranova, PF
通讯作者：
Terranova, PF