Altered ErbB receptor signaling and gene expression in cisplatin-resistant ovarian cancer
Altered ErbB receptor signaling and gene expression in cisplatin-resistant ovarian cancer
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DOI：
10.1158/0008-5472.can-04-2684
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发表时间：
2005-08-01
期刊：
影响因子：
11.2
通讯作者：
Langdon, SP
中科院分区：
文献类型：
--
作者：
Macleod, K;Mullen, P;Langdon, SP
大多数卵巢癌患者接受以铂为基础的化疗，但对这种化疗的耐药性严重限制了其整体疗效。我们已经表明，这种治疗的耐药性的发展可以修改在模型系统中的细胞信号转导反应，其中顺铂治疗改变了细胞对erbB受体家族配体的反应。顺铂耐药的卵巢癌细胞系PE 01（CDDP）是从亲本PE 01系通过暴露于增加浓度的顺铂，最终获得20倍水平的耐药性。尽管PE 01细胞由erbB受体活化配体如转化生长因子-α（TGF α）、NRG 1 α和NRG 1 β刺激生长，但PE 01（CDDP）系受TGF α和NRG 1 β的生长抑制，但不受TIRG 1 α的影响。TGF β 1促进PE 01细胞凋亡，但抑制PE 01细胞凋亡。还发现了细胞外信号调节激酶和磷脂酰肌醇3-激酶信号传导的差异，这可能与细胞对配体的反应改变有关。微阵列分析显示，相对于PE 01，PE 01（CDDP）细胞中有51个基因的mRNA增加至少2倍（包括FRA 1、ETV 4、MCM 2、AXL、MT3、TRAP 1和FANCG），而36个基因（包括IGFBP 3、TRAM 1、KHT 4和KRT 19）的mRNA减少量相似。差异显示逆转录酶-PCR鉴定了TCP 1、SLP 1、增殖细胞核抗原和ZXDA的mRNA表达改变。小干扰RNA抑制FRA 1、TCP 1和MCM 2表达与生长减少和FRA 1抑制与顺铂敏感性增强相关。通过细胞毒性暴露改变这些基因的表达可能有利于细胞的生存优势，包括信号传导途径的失调，这可能在耐药性的发展中至关重要。
The majority of ovarian cancer patients are treated with platinum-based chemotherapy, but the emergence of resistance to such chemotherapy severely limits its overall effectiveness. We have shown that development of resistance to this treatment can modify cell signaling responses in a model system wherein cisplatin treatment has altered cell responsiveness to ligands of the erbB receptor family. A cisplatin-resistant ovarian carcinoma cell line PE01(CDDP) was derived from the parent PE01 line by exposure to increasing concentrations of cisplatin, eventually obtaining a 20-fold level of resistance. Whereas PE01 cells were growth stimulated by the erbB receptor-activating ligands, such as transforming growth factor-alpha (TGF alpha), NRG1 alpha, and NRG1 beta, the PE01(CDDP) line was growth inhibited by TGF alpha and NRG1 beta but unaffected by TIRGIcc. TGF(x increased apoptosis in PE01 cells but decreased apoptosis in PE01 cells. Differences in extracellular signal - regulated kinase and phosphatidylinositol 3-kinase signaling were also found, which may be implicated in the altered cell response to ligands. Microarray analysis revealed 51 genes whose mRNA increased by at least 2-fold in PE01(CDDP) cells relative to PE01 (including FRA1, ETV4, MCM2, AXL, MT3, TRAP1, and FANCG), whereas 36 genes (including IGFBP3, TRAM1, and KHT4 and KRT19) decreased by a similar amount. Differential display reverse transcriptase-PCR identified altered mRNA expression for TCP1, SLP1, proliferating cell nuclear antigen, and ZXDA. Small interfering RNA inhibition of FRA1, TCP1, and MCM2 expression was associated with reduced growth and FRA1 inhibition with enhanced cisplatin sensitivity. Altered expression of these genes by cytotoxic exposure may pro-side survival advantages to cells including deregulation of signaling pathways, which may be critical in the development of drug resistance.