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Manganese superoxide dismutase overexpression inhibits the growth of androgen-independent prostate cancer cells

Oncogene volume 24, pages 77–89 (2005)Cite this article

Abstract

This study investigates the role of the antioxidant enzyme manganese superoxide dismutase (MnSOD) in androgen-independent human prostate cancer (PC-3) cells' growth rate in vitro and in vivo. MnSOD levels were found to be lower in parental PC-3 cells compared to nonmalignant, immortalized human prostate epithelial cells (P69SV40T). To unravel the role of MnSOD in the prostate cancer phenotype, PC-3 cells were stably transfected with MnSOD cDNA plasmid. The MnSOD protein and activity levels in clones overexpressing MnSOD were increased seven- to eightfold. These cell lines showed elongated cell doubling time, reduced anchorage-independent growth in soft agar compared to parental PC-3 (Wt) cells, and reduced growth rate of PC-3 tumor xenografts in athymic nude mice. Flow cytometric studies showed an increase in membrane potential in the MnSOD-overexpressing clone (Mn32) compared to Wt and Neo cells. Also, production of extracellular H2O2 was increased in the MnSOD-overexpressing clones. As determined by DNA cell cycle analysis, the proportion of cells in G1 phase was enhanced by MnSOD overexpression. Therefore, MnSOD not only regulates cell survival but also affects PC-3 cell proliferation by retarding G1 to S transition. Our results are consistent with MnSOD being a tumor suppressor gene in human prostate cancer.

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Abbreviations

BrdUrd:

bromodeoxyuridine

CAT:

catalase

CuZnSOD:

copper zinc superoxide dismutase

FBS:

fetal bovine serum

GPx:

glutathione peroxidase

HRP:

horseradish peroxidase

JC-1, 5,5′, 6,6′-tetrachloro-1,1′,3,3′-tetraethylbenzimidazolcarbocyanine iodide∣MnSOD:

manganese superoxide dismutase

PBS:

phosphate-buffered saline

pHPA:

para-hydroxy phenyl acetic acid

PI:

propidium iodide

Rh 123:

rhodamine 123

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Acknowledgements

We thank Dr Fredrick Domann, Dr Freya Schafer, and Sean Martin for their helpful discussions. We thank Dr Douglas Spitz for his help with antioxidant enzyme measurements. We also thank Dr Hong P Wang, Susan Walsh, and Sarita Menon for their various help; Justin Fishbaugh in the Flow Cytometry Core Facility for his help with flow techniques; and Ms Kellie Bodeker for her editorial assistance. This work was supported by NIH Grants CA 81090 and CA66081.

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Authors and Affiliations

  1. Free Radical and Radiation Biology Program – ESR Facility, University of Iowa, Iowa City, IA, 52242-1101, USA

    Sujatha Venkataraman & Garry R Buettner

  2. Department of Radiation Oncology, University of Iowa, Iowa City, IA, 52242-1101, USA

    Sujatha Venkataraman, Xiaohong Jiang, Christine Weydert, Yuping Zhang, Hannah J Zhang, Prabhat C Goswami, Larry W Oberley & Garry R Buettner

  3. Holden Comprehensive Cancer Center, University of Iowa, Iowa City, IA, 52242-1101, USA

    Prabhat C Goswami, Justine M Ritchie, Larry W Oberley & Garry R Buettner

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  1. Sujatha Venkataraman
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  2. Xiaohong Jiang
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Correspondence to Garry R Buettner.

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Venkataraman, S., Jiang, X., Weydert, C. et al. Manganese superoxide dismutase overexpression inhibits the growth of androgen-independent prostate cancer cells. Oncogene 24, 77–89 (2005). https://doi.org/10.1038/sj.onc.1208145

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