Adenovirus-mediated bax overexpression for the induction of therapeutic apoptosis in prostate cancer

X. Li, M. Marani, J. Yu, B. Nan, J. A. Roth, S. Kagawa, B. Fang, Larry Denner, M. Marcelli

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Abstract

Using adenoviral technology, we overexpressed the proapoptotic molecules pro-caspase-3, pro-caspase-7, and Bax to induce therapeutic apoptosis of prostate cancer cell lines growing in vitro and in vivo. Because overexpressed pro-caspase-3 did not undergo autocatalytic activation in any of the five prostate cancer cell lines evaluated, this strategy was unable to engage any component of the apoptotic pathway. Overexpressed procaspase-7 was proteolytically cleaved in LNCaP and LnCaP-Bcl-2 cells but not in PC-3, DU-145, or TsuPr(1) cells. Cleavage was associated with engagement of many components of the apoptotic pathway, including DEVDase activity, cleavage of intracellular caspase targets such as the DNA fragmentation factor and the proapoptotic Bid, release of cytochrome c from the mitochondria to the cytoplasm, and terminal deoxynucleotidyl transferase-mediated nick end labeling. No apoptosis was observed in the cells where caspase-7 did not undergo autocatalytic activation. Searching for an approach that would more reliably induce therapeutic apoptosis of prostate cancer cell lines, we used a binary adenoviral system to overexpress the proapoptotic molecule Bax. Bax was dramatically overexpressed and caused apoptosis of every cell line infected by engaging the mitochondrial pathway, including proteolytic cleavage and catalytic activation of the caspases, cleavage of caspase substrates, release of cytochrome c from the mitochondria, and DNA fragmentation. Furthermore, three injections of the Bax overexpression system into PC-3 cell tumors in nude mice in vivo caused a 25% regression in tumor size corresponding to a 90% reduction relative to continued tumor growth in animals that received injections with the control binary system expressing Lac-Z. These experiments show that adenovirus-mediated Bax overexpression is capable of inducing therapeutic programmed cell death in vitro and in vivo by activating the mitochondrial pathway of apoptosis. On the basis of these studies, we conclude that manipulation of Bax expression is an attractive new gene therapy approach for the treatment of prostate cancer.

Original languageEnglish (US)
Pages (from-to)186-191
Number of pages6
JournalCancer Research
Volume61
Issue number1
StatePublished - Jan 1 2001
Externally publishedYes

Fingerprint

Adenoviridae
Prostatic Neoplasms
Caspase 7
Apoptosis
Caspases
Cell Line
DNA Fragmentation
Cytochromes c
Caspase 3
Mitochondria
Therapeutics
Neoplasms
Injections
DNA Nucleotidylexotransferase
Nude Mice
Genetic Therapy
Cytoplasm
Cell Death
Technology
Growth

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Li, X., Marani, M., Yu, J., Nan, B., Roth, J. A., Kagawa, S., ... Marcelli, M. (2001). Adenovirus-mediated bax overexpression for the induction of therapeutic apoptosis in prostate cancer. Cancer Research, 61(1), 186-191.

Adenovirus-mediated bax overexpression for the induction of therapeutic apoptosis in prostate cancer. / Li, X.; Marani, M.; Yu, J.; Nan, B.; Roth, J. A.; Kagawa, S.; Fang, B.; Denner, Larry; Marcelli, M.

In: Cancer Research, Vol. 61, No. 1, 01.01.2001, p. 186-191.

Research output: Contribution to journalArticle

Li, X, Marani, M, Yu, J, Nan, B, Roth, JA, Kagawa, S, Fang, B, Denner, L & Marcelli, M 2001, 'Adenovirus-mediated bax overexpression for the induction of therapeutic apoptosis in prostate cancer', Cancer Research, vol. 61, no. 1, pp. 186-191.
Li X, Marani M, Yu J, Nan B, Roth JA, Kagawa S et al. Adenovirus-mediated bax overexpression for the induction of therapeutic apoptosis in prostate cancer. Cancer Research. 2001 Jan 1;61(1):186-191.
Li, X. ; Marani, M. ; Yu, J. ; Nan, B. ; Roth, J. A. ; Kagawa, S. ; Fang, B. ; Denner, Larry ; Marcelli, M. / Adenovirus-mediated bax overexpression for the induction of therapeutic apoptosis in prostate cancer. In: Cancer Research. 2001 ; Vol. 61, No. 1. pp. 186-191.
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