Negative regulation of chemokine receptor CXCR4 by tumor suppressor p53 in breast cancer cells: implications of p53 mutation or isoform expression on breast cancer cell invasion
Negative regulation of chemokine receptor CXCR4 by tumor suppressor p53 in breast cancer cells: implications of p53 mutation or isoform expression on breast cancer cell invasion
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DOI：
10.1038/sj.onc.1210120
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发表时间：
2007-05-17
期刊：
影响因子：
8
通讯作者：
Nakshatri, H.
中科院分区：
文献类型：
--
作者：
Mehta, S. A.;Christopherson, K. W.;Nakshatri, H.
趋化因子受体CXCR4及其配体CXCL12可能参与了乳腺癌细胞的迁移、侵袭和转移。乳腺癌中抑癌基因P53的突变与转移和侵袭性临床表型有关。在这份报告中，我们证明野生型而不是显性-负性突变体(V143A)或癌症特异性突变体(R175H或R280K)抑制CXCR4的表达。最近发现的癌症特异性P53亚型Delta 133P53也不能抑制CXCR4启动子的活性。短干扰RNA介导的P53缺失增加了含有野生型P53的MCF-7乳腺癌细胞内源性CXCR4的表达。在缺失P53的HCT116结肠癌细胞[HCT116(P53KO)]中，CXCR4启动子的基础活性是带有功能性野生型P53的HCT116细胞的10倍。通过对CXCR4启动子的缺失分析，发现了一个与环状AMP/AP-1反应元件(Cre/AP-1)同源的7个碱基对的P53抑制元件。电泳迁移率改变和染色质免疫沉淀分析显示ATF-1和cJun与Cre/AP-1元件结合。P53拯救药物PRIMA-1降低了表达R280K突变型P53的MDA-MB-231细胞中CXCR4的mRNA和细胞表面的表达。另一种拯救p53的药物CP-31398也同样降低了细胞表面CXCR4的水平。PRIMA-1介导的CXCR4表达的降低与通过Matrigel减少对MDA-MB-231细胞的侵袭有关。这些结果提示，P53突变或表达异构体的乳腺癌中CXCR4表达升高和转移的机制。我们认为，P53拯救药物单独或与化疗药物联合应用可能有效地减少CXCR4介导的转移。
Chemokine receptor CXCR4 and its ligand CXCL12 are suggested to be involved in migration, invasion and metastasis of breast cancer cells. Mutation of the tumor suppressor gene p53 in breast cancer is associated with metastasis and aggressive clinical phenotype. In this report, we demonstrate that wild type but not the dominant-negative mutant (V143A)or cancer-specific mutants (R175H or R280K) of p53 repress CXCR4 expression. Recently described cancer-specific p53 isoform, Delta 133p53, also failed to repress CXCR4 promoter activity. Short-interfering RNA-mediated depletion of p53 increased endogenous CXCR4 expression in MCF-7 breast cancer cells that contain wild-type p53. Basal CXCR4 promoter activity in HCT116 colon carcinoma cells deleted of p53 [HCT116(p53KO)] was 10-fold higher compared to that in parental HCT116 cells with functional wild-type p53. Deletion analysis of CXCR4 promoter identified a seven-base pair p53-repressor element homologous to cyclic AMP/AP-1 response (CRE/AP-1) element. Electrophoretic mobility shift and chromatin immunoprecipitation assays revealed binding of ATF-1 and cJun to the CRE/AP-1 element. The p53 rescue drug PRIMA-1 reduced CXCR4 mRNA and cell surface expression in MDA-MB-231 cells, which express R280K mutant p53. CP-31398, another p53 rescue drug, similarly reduced cell surface levels of CXCR4. PRIMA-1-mediated decrease in CXCR4 expression correlated with reduced invasion of MDA-MB-231 cells through matrigel. These results suggest a mechanism for elevated CXCR4 expression and metastasis of breast cancers with p53 mutations or isoform expression. We propose that p53 rescue drugs either alone or in combination with chemotherapeutic drugs may be effective in reducing CXCR4-mediated metastasis.