Vikhanskaya F, Clerico L, Valenti M, Stanzione M S, Broggini M, Parodi S, Russo P
Department of Experimental Oncology, Istituto Nazionale per la Ricerca sul Cancro, Genoa, Italy.
Int J Cancer. 1997 Jul 3;72(1):155-9. doi: 10.1002/(sici)1097-0215(19970703)72:1<155::aid-ijc22>3.0.co;2-h.
A possible novel mechanism of cross-resistance to cisplatin (CDDP) in the doxorubicin-resistant ovarian-cancer cell line A2780-DX3, which displays atypical multidrug resistance, is presented. A2780-DX3 is found to be more resistant than the parental line A2780 in terms of CDDP-induced cytotoxicity and apoptosis. Resistance is not related to the amount of cross-links. Topoisomerase-II (topII) protein levels were similar in both cell lines, with lower cleavage activity in A2780-DX3 cells. The parental and the doxorubicin-resistant cells expressed the same level of c-erb2, which could be implicated in CDDP resistance. bcl2 was almost undetectable in both cell lines. At the same time, we found strong induction of p53, waf-1 and bax protein levels after CDDP treatment in the A2780, but not in the A2780-DX3, cell line. Treatment of both cell lines with mitomycin C (MMC), which acts with a mechanism different from CDDP, caused equal accumulation of p53 and induction of bax. We found that A2780-DX3 cells exhibit altered cellular localization of p53 protein in comparison with A2780. A significant proportion of p53 in A2780-DX3 cells was found in the cytoplasmic compartment, and CDDP treatment induced a functional p53 protein in the nucleus of A2780 much more strongly than in A2780-DX3, which coincides with an increase of transcriptional activity of p53 in treated A2780 cells. We propose that the cross-resistance to CDDP in the A2780-DX3 cell line may be due to inactivation of a CDDP-dependent p53-accumulation pathway.
本文提出了一种在显示非典型多药耐药性的阿霉素耐药卵巢癌细胞系A2780 - DX3中对顺铂（CDDP）产生交叉耐药的可能新机制。在CDDP诱导的细胞毒性和凋亡方面，发现A2780 - DX3比亲代细胞系A2780具有更强的耐药性。耐药性与交联量无关。两种细胞系中的拓扑异构酶-II（topII）蛋白水平相似，但A2780 - DX3细胞中的切割活性较低。亲代细胞和阿霉素耐药细胞表达相同水平的c-erb2，这可能与CDDP耐药有关。两种细胞系中几乎都检测不到bcl2。同时，我们发现CDDP处理后，A2780细胞系中p53、waf-1和bax蛋白水平强烈诱导，但A2780 - DX3细胞系中未出现这种情况。用丝裂霉素C（MMC）处理这两种细胞系，MMC的作用机制与CDDP不同，会导致p53等量积累和bax诱导。我们发现，与A2780相比，A2780 - DX3细胞中p53蛋白的细胞定位发生了改变。在A2780 - DX3细胞中，很大一部分p53存在于细胞质区室，而CDDP处理在A2780细胞核中诱导功能性p53蛋白的作用比在A2780 - DX3中强得多，这与处理后的A2780细胞中p53转录活性增加一致。我们提出，A2780 - DX3细胞系对CDDP的交叉耐药可能是由于CDDP依赖的p53积累途径失活所致。
