Differential roles of phosphoinositide-dependent protein kinase-1 and Akt1 expression and phosphorylation in breast cancer cell resistance to paclitaxel, doxorubicin, and gemcitabine
Differential roles of phosphoinositide-dependent protein kinase-1 and Akt1 expression and phosphorylation in breast cancer cell resistance to paclitaxel, doxorubicin, and gemcitabine
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DOI：
10.1124/mol.106.023333
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发表时间：
2006-09-01
影响因子：
3.6
通讯作者：
Fan, Zhen
中科院分区：
文献类型：
--
作者：
Liang, Ke;Lu, Yang;Fan, Zhen
3-磷酸肌醇依赖性蛋白激酶-1（PDK 1）和Akt 1是磷脂酰肌醇-3激酶（PI 3 K）通路的两个密切相关的组分，其在乳腺癌中受到异常调节。尽管PDK 1的重要性，但与Akt 1的研究相比，很少有研究将其评估为癌症治疗的潜在靶点。我们假设PDK 1是PI 3 K通路中的一个上级靶点。为了测试这一点，我们首先使用了一个小鼠乳腺细胞系逆转录病毒感染表达人PDK 1或Akt 1的紫杉醇，阿霉素，吉西他滨治疗的比较研究。与对照细胞相比，PDK 1或Akt 1的过表达赋予了对紫杉醇或多柔比星治疗的类似抗性。然而，PDK 1过表达细胞对吉西他滨的耐药性高于Akt 1过表达细胞。接下来，我们将PDK 1和Akt 1的表达和活化特异性磷酸化与相同药物在几种人乳腺癌细胞系中的细胞毒性作用相关联。高水平磷酸化PDK 1的细胞比表达高水平磷酸化Akt 1的细胞对吉西他滨诱导的细胞凋亡更具抗性。为了进一步验证这一观察结果，我们使用小干扰RNA寡核苷酸选择性地敲低MCF 7人乳腺癌细胞中的PDK 1或Akt 1表达。我们发现，PDK 1表达的敲低比相同细胞中Akt 1表达的敲低更有效地使MCF 7细胞对吉西他滨诱导的凋亡敏感。我们的研究结果表明，PDK 1可能是一个上级替代Akt 1作为敏感的乳腺癌细胞的化疗药物，特别是吉西他滨的目标。
3-Phosphoinositide-dependent protein kinase-1 (PDK1) and Akt1 are two closely related components of the phosphatidylinositol-3 kinase (PI3K) pathway, which is aberrantly regulated in breast cancer. Despite the importance of PDK1, few studies have evaluated it as a potential target for cancer therapy compared with studies of Akt1. We hypothesized that PDK1 is a superior target in the PI3K pathway. To test this, we first used a mouse mammary cell line retrovirally infected to express human PDK1 or Akt1 for comparative studies of treatment with paclitaxel, doxorubicin, and gemcitabine. Overexpression of PDK1 or Akt1 conferred similar resistance to treatment with paclitaxel or doxorubicin compared with control cells. However, the PDK1-overexpressing cells were more resistant to gemcitabine than were the Akt1-overexpressing cells. We next correlated the expression and activation-specific phosphorylation of PDK1 and Akt1 with the cytotoxic effects of the same agents in several human breast cancer cell lines. Cells with high levels of phosphorylated PDK1 were more resistant to gemcitabine-induced apoptosis than cells expressing high levels of phosphorylated Akt1. To further validate this observation, we used small interfering RNA oligonucleotides to selectively knock down PDK1 or Akt1 expression in MCF7 human breast cancer cells. We found that knockdown of PDK1 expression sensitized MCF7 cells to gemcitabine-induced apoptosis more effectively than did knockdown of Akt1 expression in the same cells. Our findings show that PDK1 may be a superior alternative to Akt1 as a target for sensitizing breast cancer cells to chemotherapeutic agents, particularly gemcitabine.