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Differential Roles of Phosphoinositide-Dependent Protein Kinase-1 and Akt1 Expression and Phosphorylation in Breast Cancer Cell Resistance to Paclitaxel, Doxorubicin, and Gemcitabine

Departments of Experimental Therapeutics (K.L., Y.L., X.L., Z.F.) and Molecular Therapeutics (G.B.M., Z.F.), the University of Texas M. D. Anderson Cancer Center, Houston, Texas; and Department of Oncology, Lombardi Cancer Center, Georgetown University School of Medicine, Washington, DC (X.Z., R.I.G.)

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.

Address correspondence to: Dr. Zhen Fan, Department of Experimental Therapeutics, Unit 036, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030. E-mail: zfan{at}mdanderson.org

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