PDK1 inhibitor GSK2334470 synergizes with proteasome inhibitor MG‑132 in multiple myeloma cells by inhibiting full AKT activity and increasing nuclear accumulation of the PTEN protein

  • Authors:
    • Jin Zhang
    • Chunmei Yang
    • Fengping Zhou
    • Xiaohui Chen
  • View Affiliations

  • Published online on: April 12, 2018     https://doi.org/10.3892/or.2018.6369
  • Pages: 2951-2959
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Abstract

Phosphoinositide‑dependent kinase 1 (PDK1) is generally active in multiple myeloma (MM) and higher expression than other hematopoietic cells, which is associated with the drug resistance and the disease progression. Previous studies have demonstrated that PDK1 can be targeted therapeutically in MM. In the present study, we examined the combination effect of GSK2334470 (GSK‑470), a novel and highly specific inhibitor of PDK1, with proteasome inhibitor MG‑132 in MM cell lines. GSK‑470 monotherapy significantly inhibited growth of MM cell lines and induced apoptosis that was associated with the activation of both the intrinsic mitochondrial pathway and the extrinsic death receptor pathway. Moreover, GSK‑470 demonstrated synergistic growth inhibitory effects with MG‑132. Notably, treatment with these inhibitors resulted in an almost complete inhibition of phosphorylation of mammalian target of rapamycin on Ser2448 and Ser2481 and full activation of AKT. The combination therapy also caused an upregulation of PTEN and an increased nuclear accumulation of PTEN protein. Collectively, our results provide the rationale for novel combination treatment with PDK1 inhibitor and proteasome inhibitors to improve outcomes in patients with MM.
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June-2018
Volume 39 Issue 6

Print ISSN: 1021-335X
Online ISSN:1791-2431

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Spandidos Publications style
Zhang J, Yang C, Zhou F and Chen X: PDK1 inhibitor GSK2334470 synergizes with proteasome inhibitor MG‑132 in multiple myeloma cells by inhibiting full AKT activity and increasing nuclear accumulation of the PTEN protein. Oncol Rep 39: 2951-2959, 2018
APA
Zhang, J., Yang, C., Zhou, F., & Chen, X. (2018). PDK1 inhibitor GSK2334470 synergizes with proteasome inhibitor MG‑132 in multiple myeloma cells by inhibiting full AKT activity and increasing nuclear accumulation of the PTEN protein. Oncology Reports, 39, 2951-2959. https://doi.org/10.3892/or.2018.6369
MLA
Zhang, J., Yang, C., Zhou, F., Chen, X."PDK1 inhibitor GSK2334470 synergizes with proteasome inhibitor MG‑132 in multiple myeloma cells by inhibiting full AKT activity and increasing nuclear accumulation of the PTEN protein". Oncology Reports 39.6 (2018): 2951-2959.
Chicago
Zhang, J., Yang, C., Zhou, F., Chen, X."PDK1 inhibitor GSK2334470 synergizes with proteasome inhibitor MG‑132 in multiple myeloma cells by inhibiting full AKT activity and increasing nuclear accumulation of the PTEN protein". Oncology Reports 39, no. 6 (2018): 2951-2959. https://doi.org/10.3892/or.2018.6369