Potential role of transforming growth factor 1 in drug resis- tance 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 1-dependent growth inhibition and apoptosis. Addressing the question about the mechanisms responsible for the cross-resistance to cisplatin and TGF 1, we found that cisplatinand TGF 1-resistant L1210 cells possessed a decreased expression of type I TGF 1 receptor, while the expression of type II TGF 1 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 1 receptors, revealed an increased expression of Smad 6, inhibiting TGF 1 action, only in cisplatinand TGF 1-resistant L1210 cells. TGF 1 and especially the cytotoxic mistletoe agglutinin increased Smad 6 expression in TGF 1-sensitive but not in TGF 1-resistant L1210 cells. TGF 1-resistant L1210 cells also differed from TGF 1-sensitive cells by the lack of expression of the pro-apoptotic p53 protein and higher Vol. 50 No. 2/2003