Therapeutic potential of proapoptotic molecule Noxa in the selective elimination of tumor cells.
The selective elimination of tumor cells by inducing apoptosis is one of the most important issues in cancer therapy. In this context, artificial expression of the p53 tumor-suppressor gene has been an attractive approach and numerous studies have shown its efficacy in combination with other therapies such as radiation or chemotherapy. One of the critical issues for current cancer gene therapy is how to induce apoptosis in cancer cells without affecting normal cells. In the present study, we examined the potential of Noxa, a BH3-only protein with proapoptotic activity that functions downstream of the p53-mediated apoptotic pathway, to selectively induce apoptosis in tumor cells. We found that upon infection of a recombinant adenovirus contrived to express the Noxa gene, apoptosis was induced in vitro in several human breast cancer cell lines, but not in normal mammary epithelial cell lines. Furthermore, intratumoral injection of the Noxa-expressing adenovirus resulted in marked shrinkage of the transplanted tumor derived from breast cancer cells without any notable adverse effect on the surrounding normal tissue. In contrast, the expression of Puma, another BH3-only protein that also functions downstream of the p53 pathway, induced apoptosis in both cancer and normal cells. Thus, our results suggest a mechanism wherein Noxa, but not Puma, selectively induces apoptosis in human tumor cells. These data provide a new prospect for cancer therapy by the Noxa-mediated selective elimination of malignant cells.
Suzuki
Saori
S
Department of Immunology, Graduate School of Medicine, University of Tokyo, Bunkyo-ku, Tokyo, Japan.
Nakasato
Makoto
M
Shibue
Tsukasa
T
Koshima
Isao
I
Taniguchi
Tadatsugu
T
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D017209:Apoptosis / Q000235:genetics*; D001943:Breast Neoplasms / Q000235:genetics / Q000473:pathology* / Q000628:therapy*; D045744:Cell Line, Tumor; D005260:Female; D016650:Fluorescein-5-isothiocyanate / Q000378:metabolism; D005456:Fluorescent Dyes / Q000378:metabolism; D015316:Genetic Therapy; D005982:Glutathione Transferase / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D051379:Mice; D008819:Mice, Nude; D008954:Models, Biological; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D011994:Recombinant Proteins / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
D005456:Fluorescent Dyes; C498702:PMAIP1 protein, human; D019253:Proto-Oncogene Proteins c-bcl-2; D011994:Recombinant Proteins; D005982:Glutathione Transferase; D016650:Fluorescein-5-isothiocyanate