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Maspin modulates prostate cancer cell apoptotic and angiogenic response to hypoxia via targeting AKT

Oncogene volume 27, pages 7171–7179 (2008)Cite this article

Abstract

Hypoxia has been previously linked to the development of both benign prostatic hyperplasia and prostate cancer. This study investigated the effect of maspin, an extracellular matrix (ECM) tumor suppressor, on the apoptotic response of prostate cancer cells to hypoxia. Gene expression profiling of human benign and malignant prostate epithelial cells after exposure to hypoxia or normoxia revealed dramatic changes in ECM regulators. Maspin was found to be overexpressed in response to hypoxia in prostate cancer cells, but not in benign prostate cells. To dissect the contribution of maspin to tumor cell responses within a hypoxic microenvironment, we used maspin-overexpressing DU-145 human prostate cancer cells. Exposure to hypoxic conditions (1% O2) led to a significant increase in apoptosis in the DU-145 maspin cells, compared to DU-145 neo-transfectants without a significant effect on cell migration. This enhanced sensitivity to hypoxia-induced apoptosis leads to a significant suppression of tumor growth and tumor vascularity in vivo by targeting Akt and focal adhesion kinase activation. Our findings implicate maspin in prostate cancer cell response to hypoxia via recruitment of intracellular signaling partners. This study may have significance in the identification of maspin-driven therapeutic targeting in advanced metastatic prostate cancer.

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Abbreviations

BPH-1:

benign prostatic hyperplasia cells

ECM:

extracellular matrix

FAK:

focal adhesion kinase

HIF-1α:

hypoxia-inducible factor-1α

SDS-PAGE:

SDS–polyacrylamide gel electrophoresis

TGF-β:

transforming growth factor-β1

TUNEL:

terminal deoxynucleotidyl transferase biotin-dUTP nick end labeling

VEGF:

vascular endothelial growth factor

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Acknowledgements

This work was supported by a grant from the National Institutes of Health, NIH CA107575-01 (NK). We thank Menglei Zhu for expert assistance with the preparation of the figures and Lorie Howard for help with the paper submission.

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Authors and Affiliations

  1. Division of Urology, Department of Surgery, Markey Cancer Center, University of Kentucky College of Medicine, Lexington, KY, USA

    S McKenzie, S Sakamoto & N Kyprianou

  2. Department of Molecular and Cellular Biochemistry, Markey Cancer Center, University of Kentucky College of Medicine, Lexington, KY, USA

    S McKenzie, S Sakamoto & N Kyprianou

  3. Department of Pathology, Markey Cancer Center, University of Kentucky College of Medicine, Lexington, KY, USA

    S McKenzie, S Sakamoto & N Kyprianou

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  1. S McKenzie
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  2. S Sakamoto
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Correspondence to N Kyprianou.

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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc)

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McKenzie, S., Sakamoto, S. & Kyprianou, N. Maspin modulates prostate cancer cell apoptotic and angiogenic response to hypoxia via targeting AKT. Oncogene 27, 7171–7179 (2008). https://doi.org/10.1038/onc.2008.321

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