The universal characteristic of neoplastic cells is their aberrant proliferative activity with respect to growth and proliferation in normally restrictive environments in vivo. An in vitro model system has been developed in which the progression of non-neoplastic rat liver epithelial cells through specific stages of their cell cycle is absolutely dependent on extracellular Ca2+. Neoplastic derivatives of these rat liver epithelial cells are able to transit these Ca2+-dependent restriction points and thus proliferate in vitro under a normally restrictive environment. Tumor promoters are unique substances which by themselves do not induce cancer but in conjunction with subthreshold doses of carcinogens do promote cancer cells which will not only aberrantly proliferate in vivo but also in vitro in the above mentioned model system. Tumor promoters, such as 12-0-tetradecanoylphorobol-13-acetate, enable rat liver epithelial cells to overcome their Ca2+-dependent restriction points in their cell cycle with the result of poliferation under normally restrictive conditions. Preliminary evidence suggest that the mechanisms by which tumor promoters promote the acquisition of this property is related to phosphatidylinositol turnover, protein kinase C and intracellular Ca2+. Our long range goals are to identify these mechanisms and the alterations which allow this aberrant proliferative behavior to occur. It is the specific aim of this project to determine if the turnover of phosphatidylinositiol and subsequent activation of protein kinase C and increase in intracellular Ca2+ is involved in the tumor promoter effect which enables rat liver epithelial cells to overcome the normally Ca2+-induced restriction on their proliferative activity. Attainment of these objectives should allow us to begin investigations on methods to prevent or modify the carcinogenesis process.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA042942-04
Application #
3184681
Study Section
Chemical Pathology Study Section (CPA)
Project Start
1986-07-01
Project End
1991-06-30
Budget Start
1989-07-01
Budget End
1990-06-30
Support Year
4
Fiscal Year
1989
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
Zwiller, J; Sassone-Corsi, P; Kakazu, K et al. (1991) Inhibition of PDGF-induced c-jun and c-fos expression by a tyrosine protein kinase inhibitor. Oncogene 6:219-21
Dean, N M; Mordan, L J; Tse, K et al. (1991) Okadaic acid inhibits PDGF-induced proliferation and decreases PDGF receptor number in C3H/10T1/2 mouse fibroblasts. Carcinogenesis 12:665-70
Hill, T D; Boynton, A L; Dean, N M et al. (1990) Retinyl acetate inhibits platelet-derived growth factor-induced Ca2+ signals in C3H 10T1/2 fibroblasts. J Cell Physiol 144:229-36
Hill, T D; Boynton, A L (1990) Inositol tetrakisphosphate-induced sequestration of Ca2+ replenishes an intracellular pool sensitive to inositol trisphosphate. J Cell Physiol 142:163-9
Boynton, A L; Dean, N M; Hill, T D (1990) Inositol 1,3,4,5-tetrakisphosphate and regulation of intracellular calcium. Biochem Pharmacol 40:1933-9
Hill, T D; Zwiller, J; Boynton, A L (1989) Inositol 1,3,4,5-tetrakisphosphate stimulates the initiation of DNA synthesis in Ca2+-deprived rat liver cells. J Cell Physiol 140:403-7
Boynton, A L; Cooney, R V; Hill, T D et al. (1989) Extracellular ATP mobilizes intracellular Ca2+ in T51B rat liver epithelial cells: a study involving single cell measurements. Exp Cell Res 181:245-55
Hill, T D; Kindmark, H; Boynton, A L (1988) Epidermal growth factor-stimulated DNA synthesis requires an influx of extracellular calcium. J Cell Biochem 38:137-44
Hill, T D; Dean, N M; Boynton, A L (1988) Inositol 1,3,4,5-tetrakisphosphate induces Ca2+ sequestration in rat liver cells. Science 242:1176-8
Hill, T D; Campos-Gonzalez, R; Kindmark, H et al. (1988) Inhibition of inositol trisphosphate-stimulated calcium mobilization by calmodulin antagonists in rat liver epithelial cells. J Biol Chem 263:16479-84

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