Growth inhibition and protein tyrosine phosphorylation in MCF 7 breast cancer cells by a novel K vitamin

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Abstract
We have designed and chemically synthesized a novel class of K‐vitamin analogs, which mediate growth inhibition by novel mechanisms (Nishikawa et al., 1995, J Biol Chem 270:28304–28310; Ni et al., 1998, J Biol Chem 273:9906–9911). We have now found that the most potent, Cpd 5 [2‐(2‐mercaptoethanol)‐3‐methyl‐1,4‐napthoquinone], inhibits growth of doxorubicin‐resistant and doxorubicin‐sensitive breast cancer cells (MCF 7r and MCF 7w) in culture. Growth inhibition by Cpd 5 was antagonized by the thiol antioxidants glutathione and cysteine, but not by catalase or superoxide dismutase, suggesting that growth inhibition is probably via conjugation of cellular thiols. In support of this, we found that Cpd 5 inhibited the activity of thiol containing cellular protein tyrosine phosphatase (PTP) enzyme, with consequent induction of various tyrosine phosphoproteins, but not serine or tyrosine phosphoproteins. The tyrosine phosphorylation was also inhibited by exogenous glutathione or cysteine and could be enhanced by depletion of cellular glutathione by BSO. This effect of Cpd 5 on protein tyrosine phosphorylation was highly selective, however. Tyrosine phosphorylation of EGF‐R, Erb‐B2, and ERK1/2 was increased, but not that of Insulin‐R or JNK. ERK1/2 tyrosine phosphorylation and growth inhibition increased with increasing concentrations of Cpd 5. Furthermore, suppression of Cpd 5–mediated ERK1/2 phosphorylation by an ERK‐kinase inhibitor antagonized growth inhibition. These results suggest a strong correlation between ERK1/2 phosphorylation by Cpd 5 and growth inhibition. This novel K‐vitamin analog thus inhibits MCF 7 cell growth and induces selective protein tyrosine phosphorylation. J. Cell. Physiol. 185:386–393, 2000.