It is proposed to continue our studies of the mechanisms whereby retinoids can inhibit carcinogen induced neoplastic transformation. Using model in vitro systems in which chemical and physical carcinogens induce neplastic change and in which retinoids are active in preventing that change, we propose to conduct following investigations. These studies are directed towards answering two major questions which are limiting the development of retinoids as effective cancer preventive agents in the clinic: 1) how to retinoids work at the cellular and biochemical level; 2) can the potential for retinoids to act as tumor promoters be avoided? Based on previously funded work and on recent developments on cellular control mechanisms, we hypothesize that retinoids act by modulating cellular phosphorylation/dephosphorylation reactions and propose a series of experiments to test this hypothesis. At the biological level, cultures will be treated with known modulators of protein phosphorylation and their effects alone and in conjunction with retinoids on the neoplastic transformation of cells monitored. At the biochemical level the phosphorylation state of cellular proteins will be monitored. In addition we will conduct extensive studies of phosphorylation of recently described residual proteins, possibly associated with the cytoskeleton, and of the composition and phosphorylation of H1 histones. Altered phosphorylation of both these substrates could induce the pleiotropic effects of retinoids. Phamacological studies will also be conducted to determine if the tumor promoting activity of retinoic acid can be explained by its inhibitory effects on intracellular communication and if this effect can be avoided by the use of retinol-like compounds which do not possess this property. These studies should aid in the rationale development of cancer chemoprevention strategies.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA039947-04
Application #
3179354
Study Section
Chemical Pathology Study Section (CPA)
Project Start
1984-09-01
Project End
1989-12-31
Budget Start
1988-01-01
Budget End
1988-12-31
Support Year
4
Fiscal Year
1988
Total Cost
Indirect Cost
Name
University of Hawaii
Department
Type
Organized Research Units
DUNS #
121911077
City
Honolulu
State
HI
Country
United States
Zip Code
96822
Acevedo, P; Bertram, J S (1995) Liarozole potentiates the cancer chemopreventive activity of and the up-regulation of gap junctional communication and connexin43 expression by retinoic acid and beta-carotene in 10T1/2 cells. Carcinogenesis 16:2215-22
Bertram, J S; Bortkiewicz, H (1995) Dietary carotenoids inhibit neoplastic transformation and modulate gene expression in mouse and human cells. Am J Clin Nutr 62:1327S-1336S
Gibson, D F; Hossain, M Z; Goldberg, G S et al. (1994) The mitogenic effects of transforming growth factors beta 1 and beta 2 in C3H/10T1/2 cells occur in the presence of enhanced gap junctional communication. Cell Growth Differ 5:687-96
Hossain, M Z; Bertram, J S (1994) Retinoids suppress proliferation, induce cell spreading, and up-regulate connexin43 expression only in postconfluent 10T1/2 cells: implications for the role of gap junctional communication. Cell Growth Differ 5:1253-61
Bertram, J S (1993) Inhibition of chemically induced neoplastic transformation by carotenoids. Mechanistic studies. Ann N Y Acad Sci 686:161-75;discussion 175-6
Bertram, J S (1993) Cancer prevention by carotenoids. Mechanistic studies in cultured cells. Ann N Y Acad Sci 691:177-91
Asato, A E; Peng, A; Hossain, M Z et al. (1993) Azulenic retinoids: novel nonbenzenoid aromatic retinoids with anticancer activity. J Med Chem 36:3137-47
Guo, H; Acevedo, P; Parsa, F D et al. (1992) Gap-junctional protein connexin 43 is expressed in dermis and epidermis of human skin: differential modulation by retinoids. J Invest Dermatol 99:460-7
Bertram, J S (1990) The chemoprevention of human cancer: an overview. Prog Clin Biol Res 354A:345-60
Rogers, M; Berestecky, J M; Hossain, M Z et al. (1990) Retinoid-enhanced gap junctional communication is achieved by increased levels of connexin 43 mRNA and protein. Mol Carcinog 3:335-43

Showing the most recent 10 out of 17 publications