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Molecular Medicine

, Volume 20, Issue 1, pp 270–279 | Cite as

Correlation between PDZK1, Cdc37, Akt and Breast Cancer Malignancy: The Role of PDZK1 in Cell Growth through Akt Stabilization by Increasing and Interacting with Cdc37

  • Hogyoung Kim
  • Zakaria Y. Abd Elmageed
  • Christian Davis
  • Ali H. El-Bahrawy
  • Amarjit S. Naura
  • Ibrahim Ekaidi
  • Asim B. Abdel-Mageed
  • A. Hamid Boulares
Research Article

Abstract

PDZ domain containing 1 (PDZK1) is a scaffold protein that plays a role in the fate of several proteins. Estrogen can induce PDZK1 gene expression; however, our recent report showed that PDZK1 expression in the breast cancer cell line MCF-7 is indirect and involves insulin-like growth factor (IGF)-1 receptor function. Such a relationship was established in cell culture systems and human breast cancer tissues. Here we show that overexpression of PDZK1 promoted an increase in cyclin D1 and enhanced anchorage-independent growth of MCF-7 cells in the absence of 17β-estradiol, suggesting that PDZK1 harbors oncogenic activity. Indeed, PDKZ1 overexpression enhanced epidermal growth factor receptor (EGFR)-stimulated MEK/ERK1/2 signaling and IGF-induced Akt phosphorylation. PDZK1 appeared to play this role, in part, by stabilizing the integrity of the growth promoting factors Akt, human epidermal growth factor receptor 2 (Her2/Neu) and EGFR. Increased Akt levels occurred via a decrease in the ubiquitination of the kinase. PDZK1 overexpression was associated with resistance to paclitaxel/5-fluorouracil/etoposide only at low concentrations. Although the increased stability of Akt was sensitive to heat shock protein 90 (HSP90) inhibition, increased levels of the cochaperone cell division cycle 37 (Cdc37), as well as its ability to bind PDZK1, appear to play a larger role in kinase stability. Using human tissue microarrays, we show strong positive correlation between PDZK1, Akt and Cdc37 protein levels, and all correlated with human breast malignancy. There were no positive correlations between PDZK1 and Cdc37 at the mRNA levels, confirming our in vitro studies. These results demonstrate a relationship between PDZK1, Akt and Cdc37, and potentially Her2/Neu and EGFR, in breast cancer, representing a new axis that can be targeted therapeutically to reduce the burden of human breast cancer.

Notes

Acknowledgments

This work was supported in part by grant RSG-116608 from the American Cancer Society and grant HL072889 from the National Institutes of Health, as well as funds from the Louisiana Cancer Research Consortium (New Orleans, LA, USA) to AH Boulares.

Supplementary material

10020_2014_2001270_MOESM1_ESM.pdf (762 kb)
Supplementary material, approximately 762 KB.

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Authors and Affiliations

  • Hogyoung Kim
    • 1
  • Zakaria Y. Abd Elmageed
    • 2
  • Christian Davis
    • 1
  • Ali H. El-Bahrawy
    • 1
  • Amarjit S. Naura
    • 1
  • Ibrahim Ekaidi
    • 3
  • Asim B. Abdel-Mageed
    • 2
  • A. Hamid Boulares
    • 1
  1. 1.The Stanley Scott Cancer Center, Louisiana State University Health Sciences CenterSouthern University at New OrleansNew OrleansUSA
  2. 2.Department of Urology, Tulane Medical CenterSouthern University at New OrleansLouisianaUSA
  3. 3.Department of Natural SciencesSouthern University at New OrleansNew OrleansUSA

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