The induction of neoplastic transformation by chemical and physical carcinogens are be modeled in in vitro culture systems. In one of the most widely used system, the IOTI/2 assay system, the frequency of transformation can be enhanced by tumor promoters such as TPA, and inhibited by retinoids. This applicant seeks to continue studies into the mechanism of action of retinoids in inhibiting the carcinogenic process. Although retinoids are being widely used clinically, their mechanisms of action is not understood. We have recently shown that retinoids strongly induce gap junctional cell communication between normal or between neoplastic cells. This is associated with enhanced growth control of these cells. We propose that growth regulatory signals are transmitted via gap junctions. We have identified the major structural protein in 10T1/2 cells as connexin43 and find that retinoids increase cellular levels of this protein, as measured on Western blots and the message for this protein determined by Northern blotting. In contrast to retinoid effects on homologous communication, communication between normal and transformed cells is inhibited by retinoids. We propose to examine the role of retinoids in controlling the assembly of connexins into functional junctions in normal and neoplastic cells and the role of protein phosphorylation in junctional conductance. Modification of connexin phosphorylation by agents which up regulate (cAMP), or down regulate (TPA) communication will be examined. To determine the validity of this model system to the cancer chemopreventive action of retinoids in humans, we propose to examine retinoid effects on gap junctional communication in an in vitro human skin system. Communication will be measured by dye injection and electrochemical means. Induction of junctional complexes will be probed by immunofluorescence and electron microscopy. Retinoid effects in pre-neoplastic human skin cells will also be studied. These studies will aid our understanding of growth control processes in general, their aberration in neoplasia, and the mechanism of action of chemopreventive agents which are in extensive clinical use.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
2R01CA039947-06A2
Application #
3179351
Study Section
Chemical Pathology Study Section (CPA)
Project Start
1984-09-01
Project End
1994-06-30
Budget Start
1991-07-01
Budget End
1992-06-30
Support Year
6
Fiscal Year
1991
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

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