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RISS 인기검색어
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- 저자 : Bonavida, Benjamin (검색결과 1 건)
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Itakura, Masayuki,Mori, Shunsuke,Park, No-Hee,Bonavida, Benjamin Korean Academy of Oral Biology and the UCLA Dental 1999 International Journal of Oral Biology Vol.24 No.3
Dysregulation of the normal apoptotic mechanism in normal cells can directly contribute to the pathogenesis of cancer and the development of resistance of tumor cells to cytotoxic drugs and lymphocytes. We have investigated the development of resistance to immune Fas-mediated apoptotic signals in oral cell lines as a function of progression from normal towards malignancy and the sensitizing effect of actinomycin D(ActD). Several lines of oral tissues that represent different stages of progression from the normal phenotype to the malignant phenotype were examined. Normal human oral keratinocytes (NHOK)were immortalized by transfection with the recombinant human papilloma virus ((HPV)-16 DNA (HoK-16B)). These cells were subsequently exposed to benzo(a)pyrene for 7days (HOK-16B-BaP) and remained non-tumorigenic in nude mice. HOK-16B-BaP exposed for longer periods (6 months) to benzo(a)pyrene (HOK-16B-BaP-T) developed tumors in nude mice when injected subcutaneously and a cell line was developed from the tumor (HOK-16B-BaP-T1). NHOK and HOK-16B were relatively more sensitive to anti-Fas antibody (CH-11) and Fas-ligand-mediated cytotoxicity than the more advanced lines. Western blot analysis and flow cytometry showed (a) decreaded surface espression of Fas, (b) decreased expression Of P53, (c) increased expression of Bcl-2 and decreased expression of Bax, as a function of tumor cell development from the normal to the malignant phenotype. Treatment with ActD augmented both anti-Fas antibody mediated and Fas ligand mediated cytotoxicity, and significantly up-regulated the p53 protein levels without changing the Bcl-2 and Bax protein levels. Fas-associated phosphatase-1 (FAP-1) is an anti-apoptotic molecule reported to interact with Fas and can block transduction of the apoptotic signal. Western blot analysis revealed that FAP-1 protein levels were increased with progression towards malignancy and was down-regulated by treatmint with ActD. These findings demonstrate the implication of several potential mechanisms by which oral cell lines become resistant to Fas-mediated apoptosis with the development of malignancy in vitro. These include decreased expression of pro-apoptotic proteins such as surface Fas, p53, and Bax, and increased expression of anti-apoptotic proteins such as Bcl-2 and FAP-1. Sensitization to Fas-apoptosis by ActD resulted in the upregulation of p53 and down-regulation of FAP-1 protein levels.
RISS
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