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Effects of five phorbol esters on gap junctional intercellular communication, morphological transformation and
T Husøy1, S O Mikalsen, T Sanner
1Department for Environmental and Occupational Cancer, Norwegian Radium Hospital, Oslo.
Abstract:
The effects of 12-O-tetradecanoylphorbol-13-acetate (TPA), 12-deoxyphorbol-13-phenylacetate (DOPP), 12-deoxyphorbol-13-phenylacetate-20-acetate (DOPP A), sapintoxin D (SAP D) and sapintoxin A (SAP A) on the decrease in [125I]epidermal growth factor (EGF) binding (indicating protein kinase C activation), suppression of gap junctional intercellular communication (GJIC) and induction of morphological cell transformation (MCT) in Syrian hamster embryo (SHE) cells were investigated. All five phorbol esters were found to reduce [125I]EGF binding in early passage SHE cells at comparable concentrations. DOPP A was approximately 10-fold less potent in decreasing GJIC compared to the other phorbol esters in early passage SHE cells, while the compounds showed less difference in suppressing GJIC in the phorbol ester sensitive SHE cell line BPNi. The decreases in [125I]EGF binding and GJIC were found to be transient in the continuous presence of phorbol esters. All phorbol esters induced MCT in early passage SHE cells, but DOPP and DOPP A were approximately 10-fold less potent than TPA, SAP D and SAP A. Thus, there seems to be some degree of correlation, but not to a full extent, between the ability of the phorbol esters to activate PKC, decrease GJIC and to induce MCT. The results do not suggest a simple relationship between PKC activation, inhibition of GJIC and the reported tumor-promoting activities of the compounds.
Insights
Five phorbol esters activated protein kinase C (PKC) and induced cell transformation in hamster cells. However, their potency varied for inhibiting cell communication, suggesting complex relationships in tumor promotion.
Area of Science:
- Cell Biology
- Biochemistry
- Toxicology
Background:
- Phorbol esters are known activators of protein kinase C (PKC).
- PKC activation, inhibition of gap junctional intercellular communication (GJIC), and morphological cell transformation (MCT) are implicated in tumor promotion.
- Syrian hamster embryo (SHE) cells provide a model for studying these effects.
Purpose of the Study:
- To investigate the effects of five phorbol esters on PKC activation, GJIC suppression, and MCT induction in SHE cells.
- To explore the correlation between these cellular responses and potential tumor-promoting activities.
Main Methods:
- Treatment of early passage SHE cells and a sensitive cell line (BPNi) with five phorbol esters: TPA, DOPP, DOPP A, SAP D, and SAP A.
- Measurement of [125I]epidermal growth factor (EGF) binding to assess PKC activation.
- Assay of gap junctional intercellular communication (GJIC).
- Induction of morphological cell transformation (MCT) scoring.
Main Results:
- All five phorbol esters reduced [125I]EGF binding at comparable concentrations, indicating PKC activation.
- DOPP A was less potent in suppressing GJIC in early passage SHE cells compared to others.
- GJIC suppression and [125I]EGF binding reduction were transient.
- All phorbol esters induced MCT, with DOPP and DOPP A being less potent than TPA, SAP D, and SAP A.
Conclusions:
- A partial correlation exists between phorbol ester-induced PKC activation, GJIC decrease, and MCT.
- The study does not support a simple, direct relationship between PKC activation, GJIC inhibition, and the tumor-promoting activities of these compounds.