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

Abstract

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, D133p53, 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.

Annexin-1 interacts with NEMO and RIP1 to constitutively activate IKK complex and NF-κB: implication in breast cancer metastasis

“…Chemokine receptors, including CXCR4 have a critical role in metastasis, and that CXCR4, in particular, is a key receptor in the crosstalk between tumor cells and their environment (Burger and Kipps, 2006). CXCR4 expression increases progressively with increasing malignant potential, and higher expression is associated with lymph node positivity, hormone receptor negativity, Her2 overexpression and poor survival in breast cancer (Cabioglu et al, 2005;Mehta et al, 2007), and that CXCR4 can act as a biomarker for metastasis (Cabioglu et al, 2005). Interestingly, CXCR4 has been shown to be regulated by NF-kB (Palkowitsch et al, 2008) and p53 (Mehta et al, 2007).…”

“…CXCR4 expression increases progressively with increasing malignant potential, and higher expression is associated with lymph node positivity, hormone receptor negativity, Her2 overexpression and poor survival in breast cancer (Cabioglu et al, 2005;Mehta et al, 2007), and that CXCR4 can act as a biomarker for metastasis (Cabioglu et al, 2005). Interestingly, CXCR4 has been shown to be regulated by NF-kB (Palkowitsch et al, 2008) and p53 (Mehta et al, 2007). Overexpression of DN-IkBa in breast cancer cells resulted in reduced expression of CXCR4, and a corresponding loss of SDF1a-mediated migration in vitro (Helbig et al, 2003).…”

Human Nephrosclerosis Triggers a Hypoxia-Related Glomerulopathy

“…In this context, it should be noted that CXCR4 transcriptional regulation also includes HIF-and hypoxiaindependent mechanisms. [52][53][54] In FSGS, the primary pathology may be of direct glomerular origin whereas narrowing of the afferent blood vessels with consecutive glomerular hypoxia may be a central mechanism in NSC. Nuclear HIF1␣ in podocytes of NSC biopsy specimens can be seen as a biological indicator for hypoxia-associated transcriptional processes.…”

A role for p53 in the regulation of extracellular matrix metalloproteinase inducer in human cancer cells

“…Recent studies have also shown that p53 is involved in the control of motility, invasion and metastasis of cancer cells through regulating several molecular signaling pathways including RhoA-ROCK pathway, 15 SDF-1/CXCL12, 16 CXCR4. 17 Although p53 mutation is known to occur in approximately 50% of human cancers, and the roles of p53 in cancer development and progression have been extensively studied and well appreciated, how loss of p53 function contributes to cancer invasion and metastasis has not been fully understood. In the current study, we demonstrated that wild-type p53 negatively modulates the protein level of EMMPRIN through the lysosomal degradation pathway, and downregulation of EMMPRIN by p53 suppresses invasive potential of cancer cells.…”