Akt involvement in paclitaxel chemoresistance of human ovarian cancer cells
Akt involvement in paclitaxel chemoresistance of human ovarian cancer cells
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DOI：
10.1196/annals.1397.012
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发表时间：
2007-01-01
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影响因子：
--
通讯作者：
Song, Yong-Sang
中科院分区：
文献类型：
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作者：
Kim, Su-Hyeong;Juhnn, Yong-Sung;Song, Yong-Sang
紫杉醇（taxol）广泛用于包括卵巢癌在内的各种癌症的化疗。虽然紫杉醇诱导癌细胞凋亡，但其确切的作用机制仍有待确定。Akt介导的生存信号使各种癌细胞免于凋亡途径。因此，Akt被认为是治疗的令人兴奋的靶标。在这里，我们证明了Akt的抑制增加了紫杉醇诱导SKOV 3和PA-1人卵巢癌细胞凋亡的功效。MTT法检测SKOV 3和PA-1细胞对紫杉醇的敏感性。在30 nM的浓度下，PA-1细胞比SKOV 3细胞对紫杉醇更敏感。细胞凋亡伴随着细胞色素c释放到细胞质中和多聚（ADP-核糖）聚合酶（PARP）的裂解。为了进一步阐明紫杉醇诱导细胞凋亡的机制，我们比较了紫杉醇耐药的SKOV 3细胞和紫杉醇敏感的PA-1细胞之间Akt的磷酸化水平。SKOV 3细胞Akt磷酸化水平高于PA-1细胞。有趣的是，紫杉醇的治疗在两种细胞系中以时间依赖性方式降低磷酸化Akt的量。此外，通过特异性磷脂酰肌醇-3-激酶（PI 3 K）-Akt抑制剂（Wortmannin和LY 294002）抑制Akt协同增加了紫杉醇诱导的细胞凋亡在两种细胞系中的功效。这些结果表明，Akt抑制剂的添加可能会增加紫杉醇对卵巢癌患者的治疗效果。
Paclitaxel (taxol) is extensively used for chemotherapy of various cancers including ovarian cancer. Although paclitaxel induces apoptosis in cancer cells, its exact mechanism of action still remains to be determined. Akt mediates survival signals which preserve various cancer cells from apoptosis pathway. Thus, Akt is considered an exciting target for therapeutics. Here, we demonstrated that inhibition of Akt increases the efficacy of the paclitaxel-induced apoptosis in SKOV3 and PA-1 human ovarian cancer cells. The sensitivity to paclitaxel of SKOV3 and PA-1 cells was examined using the MTT assay. At a concentration of 30 nM, PA-1 cells were more sensitive to paclitaxel than SKOV3 cells. Apoptosis was accompanied by the release of cytochrome c into the cytoplasm and cleavage of poly (ADP-ribose) polymerase (PARP). To further elucidate the mechanism of apoptosis by paclitaxel, we compared the levels of phosphorylation of Akt between paclitaxel-resistant SKOV3 cells and paclitaxel-sensitive PA-1 cells. The higher level of phosphorylated Akt was shown in SKOV3 cells than in PA-1 cells. Interestingly, the treatment of paclitaxel decreased the amount of phosphorylated Akt in a time-dependent manner in both cell lines. Furthermore, inhibition of Akt by specific phosphatidyinositol-3-kinase (PI3K)-Akt inhibitors (Wortmannin, and LY294002) synergistically increased the efficacy of the paclitaxel-induced apoptosis in both cell lines. These results suggest that the addition of the Akt inhibitor may increase the therapeutic efficacy of paclitaxel for patients with ovarian cancer.