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p53 suppresses CCL2-induced subcutaneous tumor xenograft

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Tumor Biology

Abstract

Chemokine (C-C motif) ligand 2 (CCL2) has recently been found to be a key player in the pathology of many human glomerular and tubulointerstitial diseases. CCL2 has also been found to be expressed in various cancers, including human hepatoma cells, human cancer progression, and human multiple myeloma cells. Thus, the inhibition of elevated CCL2 production may provide a new avenue for therapeutic intervention in CCL2-mediated cancer diseases. A previous study has indicated that knockdown of human p53 has a strong negative impact on CCL2 induction. We therefore are interested in how p53 regulates CCL2 gene expression. In the following study, our findings indicate that p53 binds to CCL2, consequently significantly downregulating CCL2 promoter activity. Furthermore, injection of CCL2-promoting cancer cells (CCL2/A549) in p53-deficient mice for 3 weeks strongly induced subcutaneous xenograft tumor growth compared with the control. Overall, the research results support the novel role of p53 in suppression of chemokine (such as CCL2)-mediated cancer diseases.

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References

  1. Marcel V et al. Delta160p53 is a novel N-terminal p53 isoform encoded by Delta133p53 transcript. FEBS Lett. 2010;584(21):4463–8.

    Article  CAS  PubMed  Google Scholar 

  2. Rohaly G et al. A novel human p53 isoform is an essential element of the ATR-intra-S phase checkpoint. Cell. 2005;122(1):21–32.

    Article  CAS  PubMed  Google Scholar 

  3. Avery-Kiejda KA et al. Small molecular weight variants of p53 are expressed in human melanoma cells and are induced by the DNA-damaging agent cisplatin. Clin Cancer Res. 2008;14(6):1659–68.

    Article  CAS  PubMed  Google Scholar 

  4. Hofstetter G et al. Alternative splicing of p53 and p73: the novel p53 splice variant p53delta is an independent prognostic marker in ovarian cancer. Oncogene. 2010;29(13):1997–2004.

    Article  CAS  PubMed  Google Scholar 

  5. Okuda Y, Okuda M, Bernard CC. Regulatory role of p53 in experimental autoimmune encephalomyelitis. J Neuroimmunol. 2003;135(1–2):29–37.

    Article  CAS  PubMed  Google Scholar 

  6. Komarova EA et al. p53 is a suppressor of inflammatory response in mice. FASEB J. 2005;19(8):1030–2.

    CAS  PubMed  Google Scholar 

  7. Staib F et al. The p53 tumor suppressor network is a key responder to microenvironmental components of chronic inflammatory stress. Cancer Res. 2005;65(22):10255–64.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Baum N et al. The prolyl cis/trans isomerase cyclophilin 18 interacts with the tumor suppressor p53 and modifies its functions in cell cycle regulation and apoptosis. Oncogene. 2009;28(44):3915–25.

    Article  CAS  PubMed  Google Scholar 

  9. Kondo M et al. Transcription factor activating protein-2beta: a positive regulator of monocyte chemoattractant protein-1 gene expression. Endocrinology. 2009;150(4):1654–61.

    Article  CAS  PubMed  Google Scholar 

  10. Schilling M et al. Effects of monocyte chemoattractant protein 1 on blood-borne cell recruitment after transient focal cerebral ischemia in mice. Neuroscience. 2009;161(3):806–12.

    Article  CAS  PubMed  Google Scholar 

  11. Yang SJ et al. Inhibition of the chemokine (C-C motif) ligand 2/chemokine (C-C motif) receptor 2 pathway attenuates hyperglycaemia and inflammation in a mouse model of hepatic steatosis and lipoatrophy. Diabetologia. 2009;52(5):972–81.

    Article  CAS  PubMed  Google Scholar 

  12. Haringman JJ et al. A randomized controlled trial with an anti-CCL2 (anti-monocyte chemotactic protein 1) monoclonal antibody in patients with rheumatoid arthritis. Arthritis Rheum. 2006;54(8):2387–92.

    Article  CAS  PubMed  Google Scholar 

  13. Tak PP, Bresnihan B. The pathogenesis and prevention of joint damage in rheumatoid arthritis: advances from synovial biopsy and tissue analysis. Arthritis Rheum. 2000;43(12):2619–33.

    Article  CAS  PubMed  Google Scholar 

  14. McIntosh LM et al. Selective CCR2-targeted macrophage depletion ameliorates experimental mesangioproliferative glomerulonephritis. Clin Exp Immunol. 2009;155(2):295–303.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Zhang J, Lu Y, Pienta KJ. Multiple roles of chemokine (C-C motif) ligand 2 in promoting prostate cancer growth. J Natl Cancer Inst. 2010;102(8):522–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Abangan Jr RS et al. MCP1 directs trafficking of hematopoietic stem cell-derived fibroblast precursors in solid tumor. Am J Pathol. 2010;176(4):1914–26.

    Article  PubMed  PubMed Central  Google Scholar 

  17. Ajuebor MN, Swain MG, Perretti M. Chemokines as novel therapeutic targets in inflammatory diseases. Biochem Pharmacol. 2002;63(7):1191–6.

    Article  CAS  PubMed  Google Scholar 

  18. Tang X, Molina M, Amar S. p53 short peptide (p53pep164) regulates lipopolysaccharide-induced tumor necrosis factor-alpha factor/cytokine expression. Cancer Res. 2007;67(3):1308–16.

    Article  CAS  PubMed  Google Scholar 

  19. Tang X et al. p53 peptide prevents LITAF-induced TNF-alpha-mediated mouse lung lesions and endotoxic shock. Curr Mol Med. 2011;11(6):439–52.

    Article  CAS  PubMed  Google Scholar 

  20. Tang X et al. p53 is an important regulator of CCL2 gene expression. Curr Mol Med. 2012;12(8):929–43.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Tang X et al. LPS induces the interaction of a transcription factor, LPS-induced TNF-alpha factor, and STAT6(B) with effects on multiple cytokines. Proc Natl Acad Sci U S A. 2005;102(14):5132–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Zheng H et al. The prolyl isomerase Pin1 is a regulator of p53 in genotoxic response. Nature. 2002;419(6909):849–53.

    Article  CAS  PubMed  Google Scholar 

  23. Goser S et al. Critical role for monocyte chemoattractant protein-1 and macrophage inflammatory protein-1alpha in induction of experimental autoimmune myocarditis and effective anti-monocyte chemoattractant protein-1 gene therapy. Circulation. 2005;112(22):3400–7.

    Article  PubMed  Google Scholar 

  24. Scanu A et al. High-density lipoproteins downregulate CCL2 production in human fibroblast-like synoviocytes stimulated by urate crystals. Arthritis Res Ther. 2010;12(1):R23.

    Article  PubMed  PubMed Central  Google Scholar 

  25. Combadiere C et al. Combined inhibition of CCL2, CX3CR1, and CCR5 abrogates Ly6C(hi) and Ly6C(lo) monocytosis and almost abolishes atherosclerosis in hypercholesterolemic mice. Circulation. 2008;117(13):1649–57.

    Article  CAS  PubMed  Google Scholar 

  26. Ikeda Y et al. Anti-monocyte chemoattractant protein-1 gene therapy attenuates pulmonary hypertension in rats. Am J Physiol Heart Circ Physiol. 2002;283(5):H2021–8.

    Article  CAS  PubMed  Google Scholar 

  27. Bernatoniene J et al. Induction of CC and CXC chemokines in human antigen-presenting dendritic cells by the pneumococcal proteins pneumolysin and CbpA, and the role played by toll-like receptor 4, NF-kappaB, and mitogen-activated protein kinases. J Infect Dis. 2008;198(12):1823–33.

    Article  CAS  PubMed  Google Scholar 

  28. Ip WK, Wong CK, Lam CW. Interleukin (IL)-4 and IL-13 up-regulate monocyte chemoattractant protein-1 expression in human bronchial epithelial cells: involvement of p38 mitogen-activated protein kinase, extracellular signal-regulated kinase 1/2 and Janus kinase-2 but not c-Jun NH2-terminal kinase 1/2 signalling pathways. Clin Exp Immunol. 2006;145(1):162–72.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Hembruff SL et al. Loss of transforming growth factor-beta signaling in mammary fibroblasts enhances CCL2 secretion to promote mammary tumor progression through macrophage-dependent and -independent mechanisms. Neoplasia. 2010;12(5):425–33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Hu H et al. Tumor cell-microenvironment interaction models coupled with clinical validation reveal CCL2 and SNCG as two predictors of colorectal cancer hepatic metastasis. Clin Cancer Res. 2009;15(17):5485–93.

    Article  CAS  PubMed  Google Scholar 

  31. Lu X, Kang Y. Chemokine (C-C motif) ligand 2 engages CCR2+ stromal cells of monocytic origin to promote breast cancer metastasis to lung and bone. J Biol Chem. 2009;284(42):29087–96.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Tanaka K et al. The expression of monocyte chemotactic protein-1 in papillary thyroid carcinoma is correlated with lymph node metastasis and tumor recurrence. Thyroid. 2009;19(1):21–5.

    Article  CAS  PubMed  Google Scholar 

  33. Eugenin EA et al. CCL2/monocyte chemoattractant protein-1 mediates enhanced transmigration of human immunodeficiency virus (HIV)-infected leukocytes across the blood-brain barrier: a potential mechanism of HIV-CNS invasion and neuroAIDS. J Neurosci. 2006;26(4):1098–106.

    Article  CAS  PubMed  Google Scholar 

  34. Gonzalez E et al. HIV-1 infection and AIDS dementia are influenced by a mutant MCP-1 allele linked to increased monocyte infiltration of tissues and MCP-1 levels. Proc Natl Acad Sci U S A. 2002;99(21):13795–800.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Hacke K et al. Regulation of MCP-1 chemokine transcription by p53. Mol Cancer. 2010;9:82.

    Article  PubMed  PubMed Central  Google Scholar 

  36. Joerger AC et al. Structural evolution of p53, p63, and p73: implication for heterotetramer formation. Proc Natl Acad Sci U S A. 2009;106(42):17705–10.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Kaustov L et al. The conserved CPH domains of Cul7 and PARC are protein-protein interaction modules that bind the tetramerization domain of p53. J Biol Chem. 2007;282(15):11300–7.

    Article  CAS  PubMed  Google Scholar 

  38. Shaulian E et al. Tight DNA binding and oligomerization are dispensable for the ability of p53 to transactivate target genes and suppress transformation. EMBO J. 1993;12(7):2789–97.

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Slingerland JM, Jenkins JR, Benchimol S. The transforming and suppressor functions of p53 alleles: effects of mutations that disrupt phosphorylation, oligomerization and nuclear translocation. EMBO J. 1993;12(3):1029–37.

    CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgments

This work was supported by NIH grants R01 HL76081 and R01DE014079 to SA.

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Authors and Affiliations

  1. Center for Anti-Inflammatory Therapeutics, Department of Molecular & Cell Biology, Boston University Goldman School of Dental Medicine, 650 Albany Street, X-343, Boston, MA, 02118, USA

    Xiaoren Tang & Salomon Amar

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  1. Xiaoren Tang
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  2. Salomon Amar
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Correspondence to Salomon Amar.

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Tang, X., Amar, S. p53 suppresses CCL2-induced subcutaneous tumor xenograft. Tumor Biol. 36, 2801–2808 (2015). https://doi.org/10.1007/s13277-014-2906-9

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  • DOI: https://doi.org/10.1007/s13277-014-2906-9

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