The goal of this work is to understand the mechanism by which ornithine decarboxylase (ODC) activity is induced during carcinogenesis by oncogenic ras, andto define the role of ODC in this process. Results in the Progress Report show for the first time that induction of ODC activity in Ras-transformed cells requires the coordinate activation of the Raf/MEK/ERK and PI 3-kinase pathways. ODC RNA and protein are increased, with the primary regulation being post-transcriptional. We will use constitutively active forms of Ras, Raf and Akt to activate the effector pathways of interest in RIE-1 epithelial cells. These cells are appropriate since the Raf/ME/ERK and PI 3-kinase pathways cooperate in their transformation. We will use this model to study translational regulation of ODC in response to these signaling cascades, and to assess the role of sustained ODC activation in transformation, cell cycle control, and survival. We also show that inhibiting ODC with the irreversible inactivator alpha-difluoromethylornithine (DFMO) delays the onset of spontaneous tumors in mice overexpressing an active MEK mutant in the skin (K14-MEK mice), and causes regression of established tumors. To test the hypothesis that suppression of ODC blocks the promotion of target cells initiated by the Raf/MEK/ERK pathway, we will cross K14-MEK mice with two transgenic lines overexpressing antizyme (AZ), which binds to ODC and targets it for degradation. We have shown using K5-AZ and K6-AZ mice that AZ suppresses tumor growth in the two-stage model of skin carcinogenesis. The K6 promoter requires hyperproliferation for maximal expression. Since MEK overexpression causes hyperplasia, MEK/K6-AZ mice represent a model to test if ODC inhibition is effective in preventing tumor formation after establishment of a carcinogenic environment. The K5 promoter is constitutive, and MEK/K5-AZ mice have a constant expression of AZ from birth. These mice represent a chemoprevention model, in which ODC is inhibited at the time of the initiating stimulus. We will examine tumors from MEK/AZ mice to determine effects on cell cycle proteins, apoptosis, and proliferation. To specifically address the role of ODC in cell cycle progression during tumorigenesis, we will use transgenic mice that overexpress AZ and cyclin D1 in the skin. Keratinocytes from D1/AZ mice will also be used to analyze direct interactions of AZ with cyclin D1, to test whether other properties of AZ are important for deregulation of cell proliferation in tumor development.

National Institute of Health (NIH)
National Cancer Institute (NCI)
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Metabolic Pathology Study Section (MEP)
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Blair, Donald G
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Pennsylvania State University
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Nowotarski, Shannon L; Feith, David J; Shantz, Lisa M (2015) Skin Carcinogenesis Studies Using Mouse Models with Altered Polyamines. Cancer Growth Metastasis 8:17-27
Shi, Chenxu; Cooper, Timothy K; McCloskey, Diane E et al. (2012) S-adenosylmethionine decarboxylase overexpression inhibits mouse skin tumor promotion. Carcinogenesis 33:1310-8
Origanti, Sofia; Nowotarski, Shannon L; Carr, Theresa D et al. (2012) Ornithine decarboxylase mRNA is stabilized in an mTORC1-dependent manner in Ras-transformed cells. Biochem J 442:199-207
Nowotarski, Shannon L; Origanti, Sofia; Shantz, Lisa M (2011) Posttranscriptional regulation of ornithine decarboxylase. Methods Mol Biol 720:279-92
Nowotarski, Shannon L; Shantz, Lisa M (2010) Cytoplasmic accumulation of the RNA-binding protein HuR stabilizes the ornithine decarboxylase transcript in a murine nonmelanoma skin cancer model. J Biol Chem 285:31885-94
Levin, Victor A; Jochec, Jacob L; Shantz, Lisa M et al. (2007) Relationship between ornithine decarboxylase levels in anaplastic gliomas and progression-free survival in patients treated with DFMO-PCV chemotherapy. Int J Cancer 121:2279-83
Feith, David J; Shantz, Lisa M; Shoop, Paula L et al. (2007) Mouse skin chemical carcinogenesis is inhibited by antizyme in promotion-sensitive and promotion-resistant genetic backgrounds. Mol Carcinog 46:453-65
Origanti, Sofia; Shantz, Lisa M (2007) Ras transformation of RIE-1 cells activates cap-independent translation of ornithine decarboxylase: regulation by the Raf/MEK/ERK and phosphatidylinositol 3-kinase pathways. Cancer Res 67:4834-42
Feith, David J; Origanti, Sofia; Shoop, Paula L et al. (2006) Tumor suppressor activity of ODC antizyme in MEK-driven skin tumorigenesis. Carcinogenesis 27:1090-8
Kim, Sonia W; Mangold, Ursula; Waghorne, Carol et al. (2006) Regulation of cell proliferation by the antizyme inhibitor: evidence for an antizyme-independent mechanism. J Cell Sci 119:2583-91

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