The hypothesis to be tested in this Project is that the p38 MAP kinase and the PI-3-kinase, Akt as well as EGFR pathway are significant targets for the development of chemoprevention agents to inhibit UV induced non-melanoma skin cancers. We demonstrated that UVB mediated activation of the transcription factor complex, activator protein -I(AP- 1) played a functional role in UVB induced mouse skin carcinogenesis. We also showed in initiated human keratinocytes (HaCaT cells) that UVB mediated AP-1 activation in part by transcriptional activation and expression of the c-fos gene. We found that the UVB signaling pathway leading ito c-fos transcriptional activation involved activation of p38 MAP kinase and of the PI-3-kinase, Akt signaling pathway. We also investigated the regulation of expression of an important target gene, cyclooxygenase 2 (COX-2) by UVB in keratinocytes. We found that UVB mediated transcriptional regulation of the COX-2 gene through altered phosphorylation of the cyclic AMP response element binding protein and its binding to a CRE in the promoter region of the COX-2 gene. The UVB activated signaling pathways that mediated altered CREB phosphorylation were the p38 MAP kinase and PI-3- kinase, Akt pathways. Therefore, UVB signaling leading to activation of AP-1 and COX-2 involves the p38 MAP kinase and the PI-3-kinase, Akt signaling pathways.
Specific aims are: 1) to determine whether targeted expression of dominant negative p38 MAP kinase to the epidermis of transgenic mice inhibits UVB induced skin carcinogenesis 2) to determine whether targeted expression of a mutant p85 subunit of PI-3-kinase to the epidermis of transgenic mice inhibits UVB induced skin carcinogenesis 3) to utilize known inhibitors of p38 MAP kinase and the PI-3-kinase, Akt pathway as well as EGFR targeted to the skin to determine whether in vivo inhibition of these kinases inhibits UVB induced AP-1 activation and COX-2 expression 4) to utilize known inhibitors of p38 MAP kinase and the PI-3- kinase, Akt pathway as well as EGFR targeted to the skin to determine whether these effective inhibitors found in the previous specific aim will prevent the development of UVB induced non-melanoma skin cancers in a SKH-hr1 hairless mouse model and 5) to cross validate the targets for chemoprevention between mouse and human models of UVB skin carcinogenesis. These preclinical studies are designed to lead to the development of new strategies for the chemoprevention of human skin cancers.
| Blohm-Mangone, Karen; Burkett, Nichole B; Tahsin, Shekha et al. (2018) Pharmacological TLR4 Antagonism Using Topical Resatorvid Blocks Solar UV-Induced Skin Tumorigenesis in SKH-1 Mice. Cancer Prev Res (Phila) 11:265-278 |
| Knights-Mitchell, Shellie S; Romanowski, Marek (2018) Near-Infrared Activated Release of Doxorubicin from Plasmon Resonant Liposomes. Nanotheranostics 2:295-305 |
| Roh, Eunmiri; Lee, Mee-Hyun; Zykova, Tatyana A et al. (2018) Targeting PRPK and TOPK for skin cancer prevention and therapy. Oncogene 37:5633-5647 |
| Chen, Yin; Vasquez, Monica M; Zhu, Lingxiang et al. (2017) Effects of Retinoids on Augmentation of Club Cell Secretory Protein. Am J Respir Crit Care Med 196:928-931 |
| Yamamoto, Hiroyuki; Ryu, Joohyun; Min, Eli et al. (2017) TRAF1 Is Critical for DMBA/Solar UVR-Induced Skin Carcinogenesis. J Invest Dermatol 137:1322-1332 |
| Zykova, Tatyana A; Zhu, Feng; Wang, Lei et al. (2017) The T-LAK Cell-originated Protein Kinase Signal Pathway Promotes Colorectal Cancer Metastasis. EBioMedicine 18:73-82 |
| Einspahr, Janine G; Curiel-Lewandrowski, Clara; Calvert, Valerie S et al. (2017) Protein activation mapping of human sun-protected epidermis after an acute dose of erythemic solar simulated light. NPJ Precis Oncol 1: |
| Gao, Ge; Zhang, Tianshun; Wang, Qiushi et al. (2017) ADA-07 Suppresses Solar Ultraviolet-Induced Skin Carcinogenesis by Directly Inhibiting TOPK. Mol Cancer Ther 16:1843-1854 |
| Glazer, Evan S; Bartels, Peter H; Lian, Fangru et al. (2016) Quantitative histopathology identifies patients with thin melanomas who are at risk for metastases. Melanoma Res 26:261-6 |
| Franklin, Stephen J; Younis, Usir S; Myrdal, Paul B (2016) Estimating the Aqueous Solubility of Pharmaceutical Hydrates. J Pharm Sci 105:1914-1919 |
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