Suppression activity of pro-apoptotic gene products in cancer cells, a potential application for cancer gene therapy.
Overexpression of anti-apoptotic Bcl-2 and Bcl-XL proteins may play a role in the development of resistance to cancer therapy. We examined the expression of these proteins in prostate, breast, and ovarian cancer cells. We found that some of these cancer cell lines expressed high levels of Bcl-XL or Bcl-2., In order to develop an effective strategy to overcome the potential inhibition of cancer therapy by Bcl-2 and Bcl-XL, we tested the inhibitory ability of several pro-apoptotic or tumor suppressor genes in these cells. The expression of these genes induced apoptosis or suppressed cell growth with variable efficiency in these cells. Harakiri (Hrk) appears to result in the greatest induction of apoptosis or inhibition of cell growth Mtd, bax and bcl-XS were also effective in inhibiting cell growth. Furthermore, transfection of Hrk, bax, or Mtd into these cells caused significantly less colony formation than in cells transfected with p53 or BRCA1. Therefore, these results suggest that Hrk, bax, and Mtd are potent therapeutic agents for cancers expressing high levels of Bcl-2 and Bcl-XL.
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Department of Obstetrics and Gynecology, University of Michigan Comprehensive Cancer Center, Ann Arbor, Michigan 48109-0936, USA. linjia@umich.edu
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D017209:Apoptosis; D051023:BH3 Interacting Domain Death Agonist Protein; D019313:BRCA1 Protein / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology; D001943:Breast Neoplasms / Q000235:genetics; D002352:Carrier Proteins / Q000096:biosynthesis / Q000235:genetics* / Q000502:physiology; D005260:Female; D015316:Genetic Therapy; D006801:Humans; D008297:Male; D009369:Neoplasms / Q000628:therapy*; D010051:Ovarian Neoplasms / Q000235:genetics; D051059:PTEN Phosphohydrolase; D010744:Phosphoric Monoester Hydrolases / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology; D011471:Prostatic Neoplasms / Q000235:genetics; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis / Q000235:genetics* / Q000502:physiology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis / Q000235:genetics* / Q000502:physiology; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology; D025521:Tumor Suppressor Proteins; D051028:bcl-2-Associated X Protein; D051020:bcl-X Protein
C494826:BAX protein, human; C494811:BCL2L1 protein, human; D051023:BH3 Interacting Domain Death Agonist Protein; C494814:BID protein, human; D019313:BRCA1 Protein; C111858:Bok protein, mouse; D002352:Carrier Proteins; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D051028:bcl-2-Associated X Protein; D051020:bcl-X Protein; D010744:Phosphoric Monoester Hydrolases; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human