Research Goals
Defining mechanisms of skin and prostate cancer using transgenic and gene knock-out models. Protein kinase C signaling in cancer induction. Caner chemoprevention.
Research
The major goals of my laboratory research are to define the in vivo link of protein kinase C (PKC) and its associated signaling components to the development of two major human cancers, skin and prostate. PKC represents a family of at least 12 lipid-dependent serine/threonine kinases, which are differentially expressed in various tissues and play distinct roles in several signal transduction pathways which regulate a wide variety of cellular stimuli. PKC is the major receptor for the tumor promotering phorbol esters and is also activated by a variety of stress factors including ultraviolet radiation. To determine the functional specificity of PKC isoforms in mouse skin carcinogenesis, we used both PKC knockout (KO) and PKC overexpressing transgenic mice. Over a decade of research, we have found that PKCe is the key PKC isoform linked to the induction of squamous cell carcinoma, a non-melanoma human skin cancer, which can be metastatic. Also, PKCe levels correlate with the aggressiveness of several human cancers including breast, brain and prostate. We and others have shown, using both in vivo experimental animal models and human cancer-derived cell lines, that PKCe-mediated oncogenic activity correlates to its ability to promote cell survival. However, the mechanisms by which PKCe signals cell survival remain elusive. We found that Stat3, which is constitutively activated in a wide variety of human cancers, is a PKCe protein partner. PKC regulates Stat3. Our current research is aimed at defining the PKCe-Stat3 signaling complex and its link to induction and progression of human cancers with primary focus on skin and prostate models
Publications
- Aziz, M. H., Manoharan, H. T., and Verma, A. K. Protein kinase C epsilon, which sensitizes skin to sun's UV radiation-induced cutaneous damage and development of squamous cell carcinomas, associates with Stat3. Cancer Res, 67: 1385-1394, 2007.
- Aziz, M. H., Wheeler, D. L., Bhamb, B., and Verma, A. K. Protein kinase C delta overexpressing transgenic mice are resistant to chemically but not to UV radiation-induced development of squamous cell carcinomas: a possible link to specific cytokines and cyclooxygenase-2. Cancer Res, 66: 713-722, 2006.
- Verma, A. K., Wheeler, D. L., Aziz, M. H., and Manoharan, H. Protein kinase Cepsilon and development of squamous cell carcinoma, the nonmelanoma human skin cancer. Mol Carcinog, 45: 381-388, 2006.
- Wheeler, D. L., Li, Y., and Verma, A. K. Protein kinase C epsilon signals ultraviolet light-induced cutaneous damage and development of squamous cell carcinoma possibly through Induction of specific cytokines in a paracrine mechanism. Photochem Photobiol, 81: 9-18, 2005.
- Wheeler, D. L., Martin, K. E., Ness, K. J., Li, Y., Dreckschmidt, N. E., Wartman, M., Ananthaswamy, H. N., Mitchell, D. L., and Verma, A. K. Protein kinase C epsilon is an endogenous photosensitizer that enhances ultraviolet radiation-induced cutaneous damage and development of squamous cell carcinomas. Cancer Res, 64: 7756-7765, 2004.
- Jansen, A. P., Dreckschmidt, N. E., Verwiebe, E. G., Wheeler, D. L., Oberley, T. D., and Verma, A. K. Relation of the induction of epidermal ornithine decarboxylase and hyperplasia to the different skin tumor-promotion susceptibilities of protein kinase C alpha, -delta and -epsilon transgenic mice. Int J Cancer, 93: 635-643, 2001.
- Jansen, A. P., Verwiebe, E. G., Dreckschmidt, N. E., Wheeler, D. L., Oberley, T. D., and Verma, A. K. Protein kinase C-epsilon transgenic mice: a unique model for metastatic squamous cell carcinoma. Cancer Res, 61: 808-812, 2001
- Reddig, P. J., Dreckschmidt, N. E., Zou, J., Bourguignon, S. E., Oberley, T. D., and Verma, A. K. Transgenic mice overexpressing protein kinase C epsilon in their epidermis exhibit reduced papilloma burden but enhanced carcinoma formation after tumor promotion. Cancer Res, 60: 595-602, 2000.
- Tseng, C. P. and Verma, A. K. Functional expression and characterization of the mouse epitope tag-protein kinase C isoforms, alpha, beta I, beta II, gamma, delta and epsilon. Gene, 169: 287-288, 1996
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