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Elevated ornithine decarboxylase activity promotes skin tumorigenesis by stimulating the recruitment of bulge stem cells but not via toxic polyamine catabolic metabolites

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Abstract

Elevated expression of ornithine decarboxylase (ODC), the regulatory enzyme in polyamine biosynthesis, targeted to the epidermis is sufficient to promote skin tumor development following a single subthreshold dose of dimethylbenz(a)anthracene (DMBA). Since skin tumor promotion involves recruitment of hair follicle bulge stem cells harboring genetic lesions, we assessed the effect of increased epidermal ODC on recruitment of bulge stem cells in ODC-ER transgenic mice in which ODC activity is induced de novo in adult skin with 4-hydroxytamoxifen (4OHT). Bromodeoxyuridine-pulse labeling and use of K15.CrePR1;R26R;ODC-ER triple transgenic mice demonstrated that induction of ODC activity is sufficient to recruit bulge stem cells in quiescent skin. Because increased ODC activity not only stimulates proliferation but also increases reactive oxygen species (ROS) generation via subsequent induction of polyamine catabolic oxidases, we used an inhibitor of polyamine catabolic oxidase activity, MDL72527, to investigate whether ROS generation by polyamine catabolic oxidases contributes to skin tumorigenesis in DMBA-initiated ODC-ER transgenic skin. Newborn ODC-ER transgenic mice and their normal littermates were initiated with a single topical dose of DMBA. To assess tumor development originating from dormant bulge stem cells that possess DMBA-initiated mutations, epidermal ODC activity was induced in ODC-ER mice with 4OHT 5 weeks after DMBA initiation followed by MDL72527 treatment. MDL72527 treatment resulted in a shorter tumor latency time, increased tumor burden, increased conversion to carcinomas, and lower tumor levels of p53. Thus, elevated epidermal ODC activity promotes tumorigenesis by stimulating the recruitment of bulge stem cells but not via ROS generation by polyamine catabolic oxidases.

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References

  • Agostinelli E, Tempera G, Viceconte N, Saccoccio S, Battaglia V, Grancara S, Toninello A, Stevanato R (2010) Potential anticancer application of polyamine oxidation products formed by amine oxidase: a new therapeutic approach. Amino Acids 38(2):353–368

    Article  CAS  PubMed  Google Scholar 

  • Ahmad N, Gilliam AC, Katiyar SK, O’Brien TG, Mukhtar H (2001) A definitive role of ornithine decarboxylase in photocarcinogenesis. Am J Pathol 159(3):885–892

    Article  CAS  PubMed  Google Scholar 

  • Berton TR, Wang XJ, Zhou Z, Kellendonk C, Schutz G, Tsai S, Roop DR (2000) Characterization of an inducible, epidermal-specific knockout system: differential expression of lacZ in different Cre reporter mouse strains. Genesis 26(2):160–161

    CAS  PubMed  Google Scholar 

  • Bickers DR, Athar M (2006) Oxidative stress in the pathogenesis of skin disease. J Invest Dermatol 126(12):2565–2575

    Article  CAS  PubMed  Google Scholar 

  • Chen Y, Megosh LC, Gilmour SK, Sawicki JA, O’Brien TG (2000) K6/ODC transgenic mice as a sensitive model for carcinogen identification. Toxicol Lett 116(1–2):27–35

    Article  CAS  PubMed  Google Scholar 

  • Coleman CS, Pegg AE, Megosh LC, Guo Y, Sawicki JA, O’Brien TG (2002) Targeted expression of spermidine/spermine N1-acetyltransferase increases susceptibility to chemically induced skin carcinogenesis. Carcinogenesis 23(2):359–364

    Article  CAS  PubMed  Google Scholar 

  • Cotsarelis G, Sun TT, Lavker RM (1990) Label-retaining cells reside in the bulge area of pilosebaceous unit: implications for follicular stem cells, hair cycle, and skin carcinogenesis. Cell 61:1329–1337

    Article  CAS  PubMed  Google Scholar 

  • Gilmour SK, Birchler M, Smith MK, Rayca K, Mostochuk J (1999) Effect of elevated levels of ornithine decarboxylase on cell cycle progression in skin. Cell Growth Differ 10:739–748

    CAS  PubMed  Google Scholar 

  • Hayes CS, Defeo K, Dang H, Trempus CS, Morris RJ, Gilmour SK (2011) A prolonged and exaggerated wound response with elevated ODC activity mimics early tumor development. Carcinogenesis 32(9):1340–1348

    Article  CAS  PubMed  Google Scholar 

  • Hobbs CA, Paul BA, Gilmour SK (2003) Elevated levels of polyamines alter chromatin in murine skin and tumors without global changes in nucleosome acetylation. Exp Cell Res 290(2):427–436

    Article  CAS  PubMed  Google Scholar 

  • Hobbs CA, Wei G, Defeo K, Paul B, Hayes CS, Gilmour SK (2006) Tip60 protein isoforms and altered function in skin and tumors that overexpress ornithine decarboxylase. Cancer Res 66(16):8116–8122

    Article  CAS  PubMed  Google Scholar 

  • Iskander K, Gaikwad A, Paquet M, Long DJ 2nd, Brayton C, Barrios R, Jaiswal AK (2005) Lower induction of p53 and decreased apoptosis in NQO1-null mice lead to increased sensitivity to chemical-induced skin carcinogenesis. Cancer Res 65(6):2054–2058

    Article  CAS  PubMed  Google Scholar 

  • Ito M, Liu Y, Yang Z, Nguyen J, Liang F, Morris RJ, Cotsarelis G (2005) Stem cells in the hair follicle bulge contribute to wound repair but not to homeostasis of the epidermis. Nat Med 11(12):1351–1354

    Article  CAS  PubMed  Google Scholar 

  • Koza RA, Megosh LC, Palmieri M, O’Brien TG (1991) Constitutively elevated levels of ornithine and polyamines in mouse epidermal papillomas. Carcinogenesis 12(9):1619–1625

    Article  CAS  PubMed  Google Scholar 

  • Kwak MK, Kensler TW, Casero RA Jr (2003) Induction of phase 2 enzymes by serum oxidized polyamines through activation of Nrf2: effect of the polyamine metabolite acrolein. Biochem Biophys Res Commun 305(3):662–670

    Article  CAS  PubMed  Google Scholar 

  • Lan L, Hayes CS, Laury-Kleintop L, Gilmour S (2005) Suprabasal induction of ornithine decarboxylase in adult mouse skin is sufficient to activate keratinocytes. J Invest Dermatol 124:602–614

    Article  CAS  PubMed  Google Scholar 

  • Li S, Park H, Trempus CS, Gordon D, Liu Y, Cotsarelis G, Morris RJ (2012) A keratin 15 containing stem cell population from the hair follicle contributes to squamous papilloma development in the mouse. Mol Carcinog. doi: 10.1002/mc.21896. [Epub ahead of print]

  • Liu Y, Lyle S, Yang Z, Cotsarelis G (2003) Keratin 15 promoter targets putative epithelial stem cells in the hair follicle bulge. J Invest Dermatol 121(5):963–968

    Article  CAS  PubMed  Google Scholar 

  • Morris R, Argyris TS (1983) Epidermal cell cycle and transit times during hyperplastic growth induced by abrasion or treatment with 12-O-tetradecanoylphorbol-13-acetate. Cancer Res 43:4935–4942

    CAS  PubMed  Google Scholar 

  • Morris RJ, Potten CS (1999) Highly persistent label-retaining cells in the hair follicles of mice and their fate following induction of anagen. J Invest Dermatol 112(4):470–475

    Article  CAS  PubMed  Google Scholar 

  • Morris RJ, Fischer SM, Slaga TJ (1986) Evidence that a slowly cycling subpopulation of adult murine epidermal cells retains carcinogen. Cancer Res 46(6):3061–3066

    CAS  PubMed  Google Scholar 

  • Morris RJ, Tryson KA, Wu KQ (2000) Evidence that the epidermal targets of carcinogen action are found in the interfollicular epidermis of infundibulum as well as in the hair follicles. Cancer Res 60(2):226–229

    CAS  PubMed  Google Scholar 

  • Morris RJ, Liu Y, Marles L, Yang Z, Trempus C, Li S, Lin JS, Sawicki JA, Cotsarelis G (2004) Capturing and profiling adult hair follicle stem cells. Nat Biotechnol 22(4):411–417

    Article  CAS  PubMed  Google Scholar 

  • O’Brien TG (1976) The induction of ornithine decarboxylase as an early, possibly obligatory event in mouse skin carcinogenesis. Cancer Res 36:2644–2653

    PubMed  Google Scholar 

  • O’Brien TG, Megosh LC, Gilliard G, Soler AP (1997) Ornithine decarboxylase overexpression is a sufficient condition for tumor promotion in mouse skin. Cancer Res 57(13):2630–2637

    PubMed  Google Scholar 

  • Owens DM, Watt FM (2003) Contribution of stem cells and differentiated cells to epidermal tumours. Nat Rev Cancer 3(6):444–451

    Article  CAS  PubMed  Google Scholar 

  • Pegg AE (2009) Mammalian polyamine metabolism and function. IUBMB Life 61(9):880–894. doi:10.1002/iub.230

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Peralta Soler A, Gilliard G, Megosh L, George K, O’Brien TG (1998) Polyamines regulate expression of the neoplastic phenotype in mouse skin. Cancer Res 58:1654–1659

    CAS  PubMed  Google Scholar 

  • Pledgie A, Huang Y, Hacker A, Zhang Z, Woster PM, Davidson NE, Casero RA Jr (2005) Spermine oxidase SMO(PAOh1), Not N1-acetylpolyamine oxidase PAO, is the primary source of cytotoxic H2O2 in polyamine analogue-treated human breast cancer cell lines. J Biol Chem 280(48):39843–39851

    Article  CAS  PubMed  Google Scholar 

  • Scalabrino G, Pigatto P, Ferioli ME, Modena D, Puerari M, Caru A (1980) Levels of activity of the polyamine biosynthetic decarboxylases as indicators of degree of malignancy of human cutaneous epitheliomas. J Invest Dermatol 74(3):122–124

    Article  CAS  PubMed  Google Scholar 

  • Seiler N, Duranton B, Raul F (2002) The polyamine oxidase inactivator MDL 72527. Prog Drug Res 59:1–40

    CAS  PubMed  Google Scholar 

  • Shi C, Cooper TK, McCloskey DE, Glick AB, Shantz LM, Feith DJ (2012) S-adenosylmethionine decarboxylase overexpression inhibits mouse skin tumor promotion. Carcinogenesis 33(7):1310–1318

    Article  CAS  PubMed  Google Scholar 

  • Slaga TJ (1995) Inhibition of skin tumor initiation, promotion, and progression by antioxidants and related compounds. Crit Rev Food Sci Nutr 35(1–2):51–57

    Article  CAS  PubMed  Google Scholar 

  • Smith MK, Trempus CS, Gilmour SK (1998) Co-operation between follicular ornithine decarboxylase and v-Ha-ras induces spontaneous papillomas and malignant conversion in transgenic skin. Carcinogenesis 19(8):1409–1415

    Article  CAS  PubMed  Google Scholar 

  • Tani H, Morris RJ, Kaur P (2000) Enrichment for murine keratinocyte stem cells based on cell surface phenotype. Proc Natl Acad Sci USA 97(20):10960–10965

    Article  CAS  PubMed  Google Scholar 

  • Taylor G, Lehrer MS, Jensen PJ, Sun TT, Lavker RM (2000) Involvement of follicular stem cells in forming not only the follicle but also the epidermis. Cell 102(4):451–461. doi:S0092-8674(00)00050-7

    Article  CAS  PubMed  Google Scholar 

  • Trempus CS, Morris RJ, Bortner CD, Cotsarelis G, Faircloth RS, Reece JM, Tennant RW (2003) Enrichment for living murine keratinocytes from the hair follicle bulge with the cell surface marker CD34. J Invest Dermatol 120(4):501–511

    Article  CAS  PubMed  Google Scholar 

  • Trempus CS, Morris RJ, Ehinger M, Elmore A, Bortner CD, Ito M, Cotsarelis G, Nijhof JG, Peckham J, Flagler N, Kissling G, Humble MM, King LC, Adams LD, Desai D, Amin S, Tennant RW (2007) CD34 expression by hair follicle stem cells is required for skin tumor development in mice. Cancer Res 67(9):4173–4181

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Wang Y, Casero RA Jr (2006) Mammalian polyamine catabolism: a therapeutic target, a pathological problem, or both? J Biochem 139(1):17–25

    CAS  PubMed  Google Scholar 

  • Wang Y, Murray-Stewart T, Devereux W, Hacker A, Frydman B, Woster PM, Casero RA Jr (2003) Properties of purified recombinant human polyamine oxidase, PAOh1/SMO. Biochem Biophys Res Commun 304(4):605–611

    Article  CAS  PubMed  Google Scholar 

  • Wang X, Feith DJ, Welsh P, Coleman CS, Lopez C, Woster PM, O’Brien TG, Pegg AE (2007) Studies of the mechanism by which increased spermidine/spermine N1-acetyltransferase activity increases susceptibility to skin carcinogenesis. Carcinogenesis 28(11):2404–2411. doi:10.1093/carcin/bgm162

    Article  CAS  PubMed  Google Scholar 

  • Wei G, DeFeo K, Hayes CS, Woster PM, Mandik-Nayak L, Gilmour SK (2008) Elevated ornithine decarboxylase levels activate ataxia telangiectasia mutated-DNA damage signaling in normal keratinocytes. Cancer Res 68(7):2214–2222. doi:10.1158/0008-5472.CAN-07-5030

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Welsh PA, Sass-Kuhn S, Prakashagowda C, McCloskey D, Feith D (2012) Spermine synthase overexpression in vivo does not increase susceptibility to DMBA/TPA skin carcinogenesis or Min-Apc intestinal tumorigenesis. Cancer Biol Ther 13(6):358–368

    Article  CAS  PubMed  Google Scholar 

  • White AC, Tran K, Khuu J, Dang C, Cui Y, Binder SW, Lowry WE (2011) Defining the origins of Ras/p53-mediated squamous cell carcinoma. Proc Natl Acad Sci USA 108(18):7425–74230

    Article  CAS  PubMed  Google Scholar 

  • Zahedi K, Bissler JJ, Wang Z, Josyula A, Lu L, Diegelman P, Kisiel N, Porter CW, Soleimani M (2007) Spermidine/spermine N1-acetyltransferase overexpression in kidney epithelial cells disrupts polyamine homeostasis, leads to DNA damage, and causes G2 arrest. Am J Physiol Cell Physiol 292(3):C1204–C1215

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

This work was supported by National Institutes of Health grant CA70739 (S.K.G.). We are grateful to Carol S. Trempus and Rebecca J. Morris for their invaluable criticisms and advice. We would also like to thank Kristin Hayden for manuscript preparation.

Conflict of interest

The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Lankenau Institute for Medical Research, 100 Lancaster Avenue, Wynnewood, PA, 19096, USA

    Candace S. Hayes, Karen DeFeo-Mattox & Susan K. Gilmour

  2. Department of Drug Discovery and Biomedical Sciences, The Medical University of South Carolina, Charleston, SC, 29425, USA

    Patrick M. Woster

Authors
  1. Candace S. Hayes
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  2. Karen DeFeo-Mattox
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  3. Patrick M. Woster
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  4. Susan K. Gilmour
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Correspondence to Susan K. Gilmour.

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Hayes, C.S., DeFeo-Mattox, K., Woster, P.M. et al. Elevated ornithine decarboxylase activity promotes skin tumorigenesis by stimulating the recruitment of bulge stem cells but not via toxic polyamine catabolic metabolites. Amino Acids 46, 543–552 (2014). https://doi.org/10.1007/s00726-013-1559-0

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  • DOI: https://doi.org/10.1007/s00726-013-1559-0

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