Substances with tumor promoting activity, especially certain phorbol esters, have been shown to interrupt junctional intercellular communication. It is not known if this effect has any significance to the enhancement of tumor formation. In preliminary studies, TPA was found to significantly increase the percentage of small colonies (less than 200 cells) forming transformed foci in cultures of carcinogen initiated C3H/10T 1/2 cells in which transformation is dependent upon the number of cells in the initiated cell colony at confluence. TPA also inhibited the rescue from ouabain toxicity of initiated 10T 1/2 cells by ouabain-resistant normal cells. Since dibutaryl cyclic AMP was found to inhibit the transformation of initiated 10T 1/2 cells, it is proposed that the junctional intercellular communication of cAMP from normal to initiated cells can suppress transformation. The interruption of this cell-cell interaction by TPA thus permits and/or stimulates transformation. To further test this hypothesis experiments are described to determine the effect of tumor promoters on 1) colony size dependence of C3H/10T 1/2 cell transformation, 2) on rescue of ouabain sensitive initiated cells by ouabain-resistant normal cells, 3) on the intercellular transfer of 6-carboxyfluorescein, and 4) on the phosphorylation of the 27,000D major gap-junction protein. The results of these experiments should provide valuable information about the role of intercellular communication in the modulation of neoplastic transformation and the role of tumor promoters and aberrant function of the gap junction in modulating preneoplastic progression to transformation.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA038806-03
Application #
3177125
Study Section
Cellular Biology and Physiology Subcommittee 1 (CBY)
Project Start
1985-09-01
Project End
1988-08-31
Budget Start
1987-09-01
Budget End
1988-08-31
Support Year
3
Fiscal Year
1987
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