Selection and preliminary characterization of variant lines of a murine macrophage tumor resistant to the antiproliferative effects of phorbol esters.

Mar 1, 1990Cancer research

Choosing and describing mouse immune cell tumor lines that resist growth-blocking effects of phorbol esters

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Abstract

Treatment with 50 ng/ml of 12-O-tetradecanoylphorbol-13-acetate (TPA) almost completely inhibited cellular proliferation in M5076 wild-type cells.

Four cell lines were derived from M5076 wild-type cells, showing variable resistance to TPA's antiproliferative effects.
Both wild-type and the resistant TPAR-3 cell line showed a rapid and transient increase in c-fos mRNA after TPA treatment.
c-fos protein induction was significantly lower in TPAR-3 cells compared to wild-type cells after TPA treatment.
Prolonged exposure to TPA led to down-regulation of protein kinase C (PKC) in both cell lines.
The decrease in PKC levels was associated with a reduction in c-fos mRNA and protein induction.
Changes in c-fos protein expression may influence the anti-proliferative response to phorbol esters, but PKC activation and c-fos mRNA levels do not appear to affect M5076 cell growth behavior.

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Treatment of M5076 wild-type cells with 50 ng/ml of 12-O-tetradecanoylphorbol-13-acetate (TPA) almost completely inhibited cellular proliferation. Continuous culture in the presence of TPA was used to derive four lines, one polyclonal (TPAR) and three clonally derived (TPAR-1, -2, and -3), which exhibited variable resistance to the antiproliferative effects of phorbol esters. Protein kinase C (PKC) activation and c-fos expression in wild-type cells and the stably resistant line (TPAR-3) were examined after phorbol ester treatment. Both lines exhibited a comparable rapid and transient induction of c-fos mRNA expression, but induction of c-fos protein was reduced markedly in the TPAR-3 cells. Similarly in both cell lines, prolonged culture in phorbol ester produced down-regulation of PKC, as measured by inducible Mr 80,000 phosphorylation and an in vitro PKC assay. This decrease in PKC levels was paralleled by a decrease in c-fos mRNA and protein induction. Thus, c-fos expression in both wild-type and TPAR-3 cells is a consequence of PKC activation, and the development of resistance to TPA-antiproliferative effects in the TPAR-3 cell line was not linked causally to alterations in PKC levels or the c-fos mRNA induction response. The malignant capacity of the TPAR line was not reduced relative to wild-type cells. PKC activation and c-fos mRNA expression do not appear to determine changes in the in vivo or in vitro growth behavior of M5076 cells, whereas variations in c-fos protein expression may determine the anti-proliferative response to tumor-promoting phorbol esters.

Selection and preliminary characterization of variant lines of a murine macrophage tumor resistant to the antiproliferative effects of phorbol esters.

Abstract

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