Potential role of transforming growth factor beta1 in drug resistance of tumor cells.

Abstract

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 beta1-dependent growth inhibition and apoptosis. Addressing the question about the mechanisms responsible for the cross-resistance to cisplatin and TGF beta1, we found that cisplatin- and TGF beta1-resistant L1210 cells possessed a decreased expression of type I TGF beta1 receptor, while the expression of type II TGF beta1 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 beta1 receptors, revealed an increased expression of Smad 6, inhibiting TGF beta1 action, only in cisplatin- and TGF beta1-resistant L1210 cells. TGF beta1 and especially the cytotoxic mistletoe agglutinin increased Smad 6 expression in TGF beta1-sensitive but not in TGF beta1-resistant L1210 cells. TGF beta1-resistant L1210 cells also differed from TGF beta1-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 beta1 is accompanied by multiple changes in the TGF beta1 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 beta1 expression in both TGFbeta1-sensitive and -resistant L1210 cells. A hypothesis is proposed that TGFbeta1 can at least partly mediate the effect of cell-stressing agents and, thus, the development of TGF beta1 resistance may be responsible for the appearance of tumor cell refractoriness to the action of some anti-cancer drugs.

Genetic variations in the transforming growth factor-beta pathway as predictors of survival in advanced non-small cell lung cancer

“…SMAD3:rs11632964 was the initial split on the survival tree for the chemotherapy group. It is known that (36,37). Therefore, the effect of SMAD3:rs11632964 in our study is in agreement with SMAD3-SMAD4 controlled upregulation of Bim playing an important role in TGF-b -induced apoptosis (38).…”

Transforming growth factor beta‐1 enhances cytotoxic effect of doxorubicin in human lung adenocarcinoma cells of A549 line

“…Studies of TGFbeta-1 and Dx co-resistance in these cell clones are ongoing in our laboratory. Data are available that cells, resistant to DNA-damaging drug cisplatin exhibit a co-resistance to TGFbeta-1 action (Stoika et al, 2003).…”

“…TGFbeta-1 was shown to mediate irradiationinduced p53-dependent apoptosis in situ (Ewan et al, 2002). Moreover, data are available that the leukemia cells, resistant to cisplatin, DNA-damaging anti-tumor drug, develop crossresistance to TGFbeta-1 (Stoika et al, 2003). Doxorubicin (adriamycin) is an anthracycline drug widely used in anticancer chemotherapy.…”

Effect of anticancer drugs on breast cancer cells sensitive and resistant to doxorubicin: expression of mRNAs of TGF-β and its receptors

“…At the late stages of tumor progression when the tumor cells become resistant to the growth inhibition by TGF-b due to inactivation of the TGF-b signaling pathway or aberrant regulation of the cell cycle, TGF-b exhibits a pro-metastatic role [26]. Earlier it has been found that the cisplatin-resistant sub-line of murine leukemia L1210 cells possesses a cross-resistance to TGF-b 1 and the mechanism of drug resistance, based on the involvement of TGF-b 1 , has been proposed [27]. We also studied whether the above mentioned anticancer drugs can alter the expression of mRNAs for TGF-b and its receptors in the MCF-7(wt) and the MCF-7(DOX/R) cells.…”