Gagnon Véronique, Van Themsche Céline, Turner Steve, Leblanc Valérie, Asselin Eric
Department of Chemistry and Biology, Medical Biology Section, University of Quebec at Trois-Rivieres, CP 500, Trois-Rivieres, QC, Canada, G9A 5H7.
Apoptosis. 2008 Feb;13(2):259-71. doi: 10.1007/s10495-007-0165-6.
We have investigated the interrelationship between two anti-apoptotic factors, XIAP and Akt, and their role in chemoresistance of uterine cancer cells. We used one cervical cancer cell line (HeLa) and two endometrial cancer cell lines (KLE and Ishikawa) as a model. The three drugs decreased Akt and XIAP content and induced apoptosis in P-Akt-negative HeLa cells. In P-Akt1/3-positive Ishikawa cells apoptosis induction correlated with XIAP decrease. P-Akt1/2/3-positive KLE cells showed maximum chemoresistance as XIAP and Akt levels/phosphorylation remained stable in response to the three drugs, and only cisplatin could significantly induce apoptosis. We found that XIAP and Akt were functionally linked in uterine cancer cells, as downregulation of XIAP with RNAi decreased P-Akt levels, and inhibition of PI3-K/Akt activity using LY294002 decreased XIAP content. Overexpression of constitutively active Akt isoforms in HeLa cells induced isoform-specific sensitivity to doxorubicin and taxol but not cisplatin. XIAP RNAi increased the cell-specific sensitivity to cisplatin and doxorubicin but not taxol. Finally, we found P-Akt immunoreactivity in epithelial cells from multiple human endometrial carcinoma tumors, suggesting that Akt may also regulate chemosensitivity in uterine cancers in vivo. Altogether these results highlight an intertwined role for specific Akt isoforms and XIAP in chemoresistance of uterine cancer cells.
我们研究了两种抗凋亡因子XIAP和Akt之间的相互关系及其在子宫癌细胞化疗耐药中的作用。我们使用一种宫颈癌细胞系（HeLa）和两种子宫内膜癌细胞系（KLE和Ishikawa）作为模型。这三种药物降低了Akt和XIAP的含量，并诱导P-Akt阴性的HeLa细胞凋亡。在P-Akt1/3阳性的Ishikawa细胞中，凋亡诱导与XIAP的降低相关。P-Akt1/2/3阳性的KLE细胞表现出最大的化疗耐药性，因为XIAP和Akt的水平/磷酸化在这三种药物作用下保持稳定，只有顺铂能显著诱导凋亡。我们发现XIAP和Akt在子宫癌细胞中存在功能联系，因为用RNAi下调XIAP会降低P-Akt水平，而使用LY294002抑制PI3-K/Akt活性会降低XIAP含量。在HeLa细胞中组成型激活的Akt亚型的过表达诱导了对阿霉素和紫杉醇而非顺铂的亚型特异性敏感性。XIAP RNAi增加了对顺铂和阿霉素而非紫杉醇的细胞特异性敏感性。最后，我们在多个人类子宫内膜癌肿瘤的上皮细胞中发现了P-Akt免疫反应性，这表明Akt在体内子宫癌中也可能调节化疗敏感性。总之，这些结果突出了特定的Akt亚型和XIAP在子宫癌细胞化疗耐药中的交织作用。
