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Autocrine motility-stimulatory pathways of oral premalignant lesion cells

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Abstract

Patients with premalignant oral lesions have varying levels of risk of developing oral squamous cell carcinoma (OSCC), whose aggressiveness requires increased motility. Not known is if and how premalignant oral lesion cells acquire the increased motility characteristic of OSCC. This was addressed by immunohistochemical analysis of banked premalignant lesion tissues and by functional analyses using cultures established from premalignant oral lesions and OSCC. These studies showed premalignant oral lesion cells and OSCC to be more motile than normal keratinocytes. Concomitantly, levels of ceramide were reduced. The activity of the protein phosphatase PP-2A, which restricts motility and which can be activated by ceramide, was also diminished. This was due to IL-10 released from premalignant lesion cells. Treatment with a membrane-permeable ceramide restored PP-2A activity and blocked migration. These studies show an autocrine motility-stimulatory pathway that is mediated in premalignant lesion cells by IL-10 through its reduction of ceramide levels and inhibition of PP-2A activity.

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References

  1. Neville BW, Day TA (2002) Oral cancer and precancerous lesions. CA Cancer J Clin 52:195–215

    Article  PubMed  Google Scholar 

  2. Epstein JB, Zhang L, Rosin M (2002) Advances in the diagnosis of oral premalignant and malignant lesions. J Can Dent Assoc 68:617–621

    PubMed  Google Scholar 

  3. Massarelli E, Liu DD, Lee JJ et al (2005) Akt activation correlates with adverse outcome in tongue cancer. Cancer 104:2430–2436

    Article  PubMed  CAS  Google Scholar 

  4. Turatti E, da Costa NA, de Magalhaes MH et al (2005) Assessment of c-Jun, c-Fos and cyclin D1 in premalignant and malignant oral lesions. J Oral Sci 47:71–76

    Article  PubMed  CAS  Google Scholar 

  5. Raimondi A, Cabrini R, Itoiz ME (2005) Ploidy analysis of field cancerization and cancer development in the hamster cheek pouch carcinogenesis model. J Oral Pathol Med 34:227–231

    Article  PubMed  CAS  Google Scholar 

  6. Bouquot JE, Whitaker SB (1994) Oral leukoplakia - rationale for diagnosis and prognosis of its clinical subtypes or “phases”. Quintessence Int 25:133–140

    PubMed  CAS  Google Scholar 

  7. Wells A (2000) Tumor invasion: role of growth factor-induced cell motility. Adv Cancer Res 78:31–101

    PubMed  CAS  Google Scholar 

  8. Young MRI, Liu SW, Meisinger J (2001) Differences in association of the serine/threonine protein phosphatase PP-2A with microtubules of metastatic and nonmetastatic tumor cells. Clin Exp Met 18:407–413

    Article  Google Scholar 

  9. Otto T, Lummen G, Be A et al (1999) Tumor cell motility. A novel therapeutic target in bladder carcinoma, experimental and clinical results. Adv Exp Med Biol 462:469–476

    PubMed  CAS  Google Scholar 

  10. Jackson J, Meisinger J, Patel S et al (1997) Protein phosphatase-2A associates with the cytoskeleton to maintain cell spreading and reduced motility of nonmetastatic Lewis lung carcinoma cells; the loss of this regulatory control in metastatic cells. Invasion Metastasis 17:199–209

    PubMed  CAS  Google Scholar 

  11. Maier GD, Wright MA, Lozano Y et al (1995) Regulation of cytoskeletal organization in tumor cells by protein phosphatases-1 and -2A. Int J Cancer 61:51–54

    Article  Google Scholar 

  12. Romashko AA, Young MRI (2004) Protein phosphatase-2A maintains focal adhesion complexes in keratinocytes and the loss of this regulation in squamous cell carcinomas. Clin Exp Met 21:371–379

    Article  CAS  Google Scholar 

  13. Young MRI, Liu SW, Meisinger J (2003) Protein phosphatase-2A restricts migration of Lewis lung carcinoma cells by modulating the phosphorylation of focal adhesion proteins. Int J Cancer 103:38–44

    Article  PubMed  CAS  Google Scholar 

  14. Dobrowsky RT, Kamibayashi C, Mumby MC et al (1993) Ceramide activates heterotrimeric protein phosphatase 2A. J Biol Chem 268:15523–15530

    PubMed  CAS  Google Scholar 

  15. Prinetti A, Bassi R, Riboni L et al (1997) Involvement of a ceramide activated protein phosphatase in the differentiation of neuroblastoma neuro2a cells. FEBS Lett 414:475–479

    Article  PubMed  CAS  Google Scholar 

  16. Seelan RS, Qian C, Yokomizo A et al (2000) Human acid ceramidase is overexpressed but not mutated in prostate cancer. Genes Chromosomes Cancer 29:137–146

    Article  PubMed  CAS  Google Scholar 

  17. Visnjic D, Batinic D, Banfic H (1999) Different roles of protein kinase C α and δ isoforms in the regulation of neutral sphingomyelinase activity in HL-60 cells. Biochem J 344:921–928

    Article  PubMed  CAS  Google Scholar 

  18. Kleuser B, Cuvillier O, Spiegel S (1998) 1α,25-dihydroxyvitamin D3 inhibits programmed cell death in HL-60 cells by activation of sphingosine kinase. Cancer Res 58:1817–1824

    PubMed  CAS  Google Scholar 

  19. Metz R, Vellody K, Patel S et al (1997) Vitamin D3 and ceramide reduce the invasion of tumor cells through extracellular matrix components by elevating protein phosphatase-2A. Invasion Metastatis 16:280–290

    Google Scholar 

  20. Young MR (2004) Tumor-derived prostaglandin E2 and transforming growth factor-β stimulate endothelial cell motility through inhibition of protein phosphatase-2A and involvement of PTEN and phosphatidylinositide 3-kinase. Angiogenesis 7:123–131

    Article  PubMed  CAS  Google Scholar 

  21. Hardie DG, Haystead AJ, Sim ATR (1991) Use of okadaic acid to inhibit protein phosphatases in intact cells. Meth Enzymol 201:469–476

    Article  PubMed  CAS  Google Scholar 

  22. Chalfant CE, Szulc Z, Roddy P et al (2004) The structural requirements for ceramide activation of serine-threonine protein phosphatases. J Lipid Res 45:496–506

    Article  PubMed  CAS  Google Scholar 

  23. Pahan K, Khan M, Singh I (2000) Interleukin-10 and interleukin-13 inhibit proinflammatory cytokine-induced ceramide production through the activation of phosphatidylinositol 3-kinase. J Neurochem 75:576–582

    Article  PubMed  CAS  Google Scholar 

  24. Jackson JL, Young MR (2002) Protein phosphatase-2A modulates the serine and tyrosine phosphorylation of paxillin in Lewis lung carcinoma tumor variants. Clin Exp Met 19:409–415

    Article  CAS  Google Scholar 

  25. Alphonse G, Bionda C, Aloy MT et al (2004) Overcoming resistance to gamma-rays in squamous carcinoma cells by poly-drug elevation of ceramide levels. Oncogene 23:2703–2715

    Article  PubMed  CAS  Google Scholar 

  26. Singh I, Pahan K, Khan M et al (1998) Cytokine-mediated induction of ceramide production is redox-sensitive. Implications to proinflammatory cytokine-mediated apoptosis in demyelinating diseases. J Biol Chem 273:20354–20362

    Article  PubMed  CAS  Google Scholar 

  27. Jarnicki AG, Lysaght J, Todryk S et al (2006) Suppression of antitumor immunity by IL-10 and TGF-β-producing T cells infiltrating the growing tumor: influence of tumor environment on the induction of CD4+ and CD8+ regulatory T cells. J Immunol 177:896–904

    PubMed  CAS  Google Scholar 

  28. Chandler SW, Rassekh CH, Rodman SM et al (2002) Immunohistochemical localization of interleukin-10 in human oral and pharyngeal carcinomas. Laryngoscope 112:808–815

    Article  PubMed  CAS  Google Scholar 

  29. Vazquez F, Grossman SRF, Takahashi Y et al (2002) Phosphorylation of the PTEN tail acts as an inhibitory switch by preventing its recruitment into a protein complex. J Biol Chem 276:48627–48630

    Article  CAS  Google Scholar 

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Acknowledgments

We are grateful to the technical assistance of Bridgette Ransom, Sarah Camens, Kim Sutton, Jarrett Walsh and Adam Mailloux in these studies. This study was supported in part by the Medical Research Service of the Department of Veterans Affairs, and by Grants CA85266 and CA97813 from the National Institutes of Health.

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Authors and Affiliations

  1. Research Service (151), Ralph H. Johnson VA Medical Center, Ralph H. Johnson Veterans Affairs Hospital, 109 Bee Street, Charleston, SC, 29401-5799, USA

    M. Rita I. Young & Deanne M. R. Lathers

  2. Department of Otolaryngology – Head and Neck Surgery, Medical University of South Carolina, 135 Rutledge Avenue, Charleston, SC, 29425, USA

    M. Rita I. Young, Deanne M. R. Lathers, M. Boyd Gillespie & Terry A. Day

  3. Department of Medicine, Medical University of South Carolina, 96 Jonathan Lucas Street, Charleston, SC, 29425, USA

    M. Rita I. Young

  4. Department of Stomatology, Medical University of South Carolina, 173 Ashley Avenue, Charleston, SC, 29425, USA

    Brad W. Neville & Angela C. Chi

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  1. M. Rita I. Young
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  2. Brad W. Neville
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  3. Angela C. Chi
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Correspondence to M. Rita I. Young.

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Young, M.R.I., Neville, B.W., Chi, A.C. et al. Autocrine motility-stimulatory pathways of oral premalignant lesion cells. Clin Exp Metastasis 24, 131–139 (2007). https://doi.org/10.1007/s10585-007-9063-0

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  • DOI: https://doi.org/10.1007/s10585-007-9063-0

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