Potential role of transforming growth factor β1 in drug resistance of tumor cells.

Acquired drug resistance of tumor cells is frequently observed in cancer patients undergoing chemotherapy. We studied murine leukemia L1210 cells sensitive and resistant to the cytotoxic action of cisplatin and showed that cisplatin-resistant leukemia cells were also refractory to TGF β1-dependent growth inhibition and apoptosis. Addressing the question about the mechanisms responsible for the cross-resistance to cisplatin and TGF β1, we found that cisplatin- and TGF β1-resistant L1210 cells possessed a decreased expression of type I TGF β1 receptor, while the expression of type II TGF β1 receptor was not affected. Western blot analysis of Smad proteins 2, 3, 4, 6, and 7, which participate in signal transduction pathway down-stream of the TGF b1 receptors, revealed an increased expression of Smad 6, inhibiting TGF b1 action, only in cisplatin- and TGF β1-resistant L1210 cells. TGF β1 and especially the cytotoxic mistletoe agglutinin increased Smad 6 expression in TGF β1-sensitive but not in TGF β1-resistant L1210 cells. TGF β1-resistant L1210 cells also differed from TGF β1-sensitive cells by the lack of expression of the pro-apoptotic p53 protein and higher level of expression of the anti-apoptotic Bcl-2 protein. Thus, the described co-expression of tumor cell refractoriness to an anti-cancer drug and to the inhibitory cytokine TGF β1 is accompanied by multiple changes in the TGF β1 signal transduction pathway and in other regulatory systems of the target cells. Besides, we found that various anti-tumor drugs and cytotoxic plant lectins increased the level of TGF b1 expression in both TGF β1-sensitive and -resistant L1210 cells. A hypothesis is proposed that TGF β1 can at least partly mediate the effect of cell-stressing agents and, thus, the development of TGF β1 resistance may be responsible for the appearance of tumor cell refractoriness to the action of some anti-cancer drugs.