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Bcl-2 and Bcl-xL differentially protect human prostate cancer cells from induction of apoptosis by melanoma differentiation associated gene-7, mda-7/IL-24

Oncogene volume 22, pages 8758–8773 (2003)Cite this article

Abstract

Subtraction hybridization identified melanoma differentiation associated gene-7, mda-7, in the context of terminally differentiated human melanoma cells. Based on its structure, cytokine-like properties and proposed mode of action, mda-7 has now been classified as IL-24. When expressed by means of a replication-incompetent adenovirus, Ad.mda-7 induces apoptosis in a broad range of cancer cells, without inducing harmful effects in normal fibroblast or epithelial cells. These unique properties of mda-7/IL-24 suggest that this gene will prove beneficial for cancer gene therapy. We now demonstrate that Ad.mda-7 decreases viability by induction of apoptosis in hormone-responsive (LNCaP) and hormone-independent (DU-145 and PC-3) human prostate carcinomas, without altering growth or survival in early-passage normal human prostate epithelial cells (HuPEC). Ad.mda-7 causes G2/M arrest and apoptosis in LNCaP (p53-wildtype), DU-145 (p53 mutant, Bax-negative) and PC-3 (p53-negative) prostate carcinomas, but not in HuPEC. Apoptosis induction correlated with changes in the ratio of pro- to antiapoptotic Bcl-2 protein family members. A potential functional role for changes in bcl-2 family gene expression in Ad.mda-7-induced apoptosis was suggested by the finding that forced overexpression of bcl-xL or bcl-2 differentially diminished the apoptotic effect of Ad.mda-7 in prostate carcinomas. These results confirm that induction of apoptosis by the mda-7/IL-24 gene in prostate cancer cells is Bax- and p53-independent and is mediated by mitochondrial pathways involving bcl-2 family gene members. The mda-7/IL-24 gene represents a new class of cancer-specific apoptosis-inducing genes with obvious potential for the targeted gene-based therapy of human prostate cancer.

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Acknowledgements

The present research was supported in part by National Cancer Institute Grants CA35675 and CA97318, DOD Prostate Cancer Research Program DAMD17-02-1-0041, DK52825, CA88906, BC98-0148, an award from the Samuel Waxman Cancer Research Foundation and the Michael and Stella Chernow Endowment. We thank Dr Sunil Chada, Introgen Therapeutics Inc., TX for providing CAR monoclonal antibody. PB Fisher is the Michael and Stella Chernow Urological Cancer Research Scientist in the Departments of Pathology, Neurosurgery and Urology. P Dent is the Universal Leaf Corporation Professor.

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Authors and Affiliations

  1. Department of Pathology, Herbert Irving Comprehensive Cancer Center, Columbia University, College of Physicians and Surgeons, New York, 10032, NY, USA

    Irina V Lebedeva, Devanand Sarkar, Zao-Zhong Su & Paul B Fisher

  2. The Burnham Institute, La Jolla, 92037, CA, USA

    Shinichi Kitada & John C Reed

  3. Department of Radiation Oncology, Virginia Commonwealth University, Richmond, 23298, VA, USA

    Paul Dent

  4. Department of Medicine, Herbert Irving Comprehensive Cancer Center, Columbia University, College of Physicians and Surgeons, New York, 10032, NY, USA

    C A Stein

  5. Department of Urology, Herbert Irving Comprehensive Cancer Center, Columbia University, College of Physicians and Surgeons, New York, 10032, NY, USA

    Paul B Fisher

  6. Department of Neurosurgery, Herbert Irving Comprehensive Cancer Center, Columbia University, College of Physicians and Surgeons, New York, 10032, NY, USA

    Paul B Fisher

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  1. Irina V Lebedeva
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  2. Devanand Sarkar
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Correspondence to Paul B Fisher.

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Lebedeva, I., Sarkar, D., Su, ZZ. et al. Bcl-2 and Bcl-xL differentially protect human prostate cancer cells from induction of apoptosis by melanoma differentiation associated gene-7, mda-7/IL-24. Oncogene 22, 8758–8773 (2003). https://doi.org/10.1038/sj.onc.1206891

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