The research in Dr. Thomas Slaga's laboratory is focused on glucocorticoid hormones (GC), very potent inhibitors of physiological DNA synthesis in keratinocytes in vivo. These hormones are also very effective in preventing carcinogen- and tumor promoter-induced skin hyperplasia, inflammation, and mouse skin tumor formation when applied to skin together with a carcinogen or a tumor promoter. We and others have shown, however, that the GC do not affect the growth of either established papillomas, squamous cell carcinomas (SCC), or transformed keratinocytes in vitro. In addition, we recently found that the GC do not affect glucocorticoid-responsive genes in transformed keratinocytes both in vitro and in vivo. We have generated skin-targeted transgenic mice over-expressing the GR under the control of the keratin 5 (K5) promoter. These adult transgenic mice have impaired proliferative and inflammatory responses to skin tumor promoters. Our initial studies showed that the K5.GR transgenic animals are resistant to ras-induced tumorigenesis. The constitutively nuclear overexpression and activation of the GR in the epidermis dramatically inhibited skin tumor development in K5.GR/ras+ double transgenic mice in terms of number of animals that develop tumors, number of tumors per animal, and tumor size. In another study we plan to determine the mechanism(s) of synergistic action of the natural source compounds, known to inhibit one or more stages of skin carcinogenesis, i.e., initiation and promotion/progression. The concurrent topical and systemic (i.e., dietary) treatment with selected natural source inhibitors of different stages of skin carcinogenesis result in synergistic effects leading to more efficient prevention of skin cancer. The natural source inhibitors to be tested include ellagic acid, imperatorin from the family of coumarins, proanthocyanidin B-2-gallate, (-)-epigallocatechin from the family of green tea polyphenols, N-acetylcysteine, calcium D-glucarate, lycopene, carnosol and ursolic acid from rosemary extract, and resveratrol. We propose to initially utilize a number of very predictive short-term in vitro and in vivo tests in order to identify the
mechanism(s) and to differentiate the potencies of selected inhibitors at various concentrations under standard conditions. The most effective compounds will then be studied in long-term tumor experiments utilizing a 7,12-dimethylbenz[a]anthracene (DMBA)-induced 12-O-tetradecanoylphorbol-13-acetate (TPA)-promoted multistage carcinogenesis model in SENCAR mice.
Selected Publications
Garcia GE, Wisniewski HG, Lucia MS, Arevalo N, Slaga TJ, Kraft SL, Strange R, Kumar AP. 2-Methoxyestradiol inhibits prostate tumor development in transgenic adenocarcinoma of mouse prostate: role of tumor necrosis factor-alpha-stimulated gene 6. Clin Cancer Res. 12:980-988, 2006.
Curtin GM, Hanausek M, Walaszek Z, Zoltaszek R, Swauger JE, Mosberg AT, Slaga TJ. Short-term biomarkers of cigarette smoke condensate tumor promoting potential in mouse skin. Toxicol Sci. 89:66-74, 2006.
Ghosh R, Nadiminty N, Fitzpatrick JE, Alworth WL, Slaga TJ, Kumar AP. Eugenol causes melanoma growth suppression through inhibition of E2F1 transcriptional activity. J Biol Chem. 280(7):5812-5819, 2005.
Curtin GM, Hanausek M, Walaszek Z, Mosberg AT, Slaga TJ. Short-term in vitro and in vivo analyses for assessing the tumor-promoting potentials of cigarette smoke condensates. Toxicol Sci. 81:14-25, 2004.
Hanausek M, Walaszek Z, Viaje A, LaBate M, Spears E, Farrell D, Henrich R, Tveit A, Walborg EF Jr, Slaga TJ. Exposure of mouse skin to organic peroxides: subchronic effects related to carcinogenic potential. Carcinogenesis. 25:431-437, 2004.
Walaszek Z, Hanausek M, Narog M, Raich PC, Slaga TJ. Mechanisms of lung cancer chemoprevention by D-glucarate. Chest 125(5 Suppl):149S-50S, 2004.
Walaszek Z, Hanausek M, Slaga TJ. Mechanisms of chemoprevention. Chest. 125(5 Suppl):128S-33S, 2004.
Budunova IV, Kowalczyk D, Perez P, Yao YJ, Jorcano JL, Slaga TJ. Glucocorticoid receptor functions as a potent suppressor of mouse skin carcinogenesis. Oncogene. 22:3279-3287, 2003.
Ghosh R, Ott AM, Seetharam D, Slaga TJ Kumar AP. Cell cycle block and apoptosis induction in a human melanoma cell line following treatment with 2-methoxyoestradiol: therapeutic implications? Melanoma Res. 13:119-127, 2003.
Kumar AP, Garcia GE, Orsborn J, Levin VA, Slaga TJ. 2-Methoxyestradiol interferes with NF kappa B transcriptional activity in primitive neuroectodermal brain tumors: implications for management. Carcinogenesis. 24:209-216, 2003.
Hanausek M, Walaszek Z, Slaga TJ. Detoxifying cancer causing agents to prevent cancer. Integr Cancer Ther. 2:139-144, 2003.
Gasparian AV, Yao YJ, Lu J, Yemelyanov AY, Lyakh LA, Slaga TJ Budunova IV. Selenium compounds inhibit I kappa B kinase (IKK) and nuclear factor-kappa B (NF-kappa B) in prostate cancer cells. Mol Cancer Ther. 1:1079-1087, 2002.
Perez P, Page A, Bravo A, Del Rio M, Gimenez-Conti I, Budunova I, Slaga TJ Jorcano JL. Altered skin development and impaired proliferative and inflammatory responses in transgenic mice overexpressing the glucocorticoid receptor. FASEB J. 15(11):2030-2032, 2001.
Kumar AP, Garcia GE, Slaga TJ. 2-methoxyestradiol blocks cell-cycle progression at G(2)/M phase and inhibits growth of human prostate cancer cells. Mol Carcinog. 2001 Jul;31(3):111-24.
Spiegelman VS, Stavropoulos P, Latres E, Pagano M, Ronai Z, Slaga TJ, Fuchs SY. Induction of beta-transducin repeat-containing protein by JNK signaling and its role in the activation of NF-kappaB. J Biol Chem. 20;276:27152-27158, 2001.
