The in vivo apoptotic effect of interferon alfa-2b on rat preneoplastic liver involves Bax protein.
To determine whether interferon alfa (IFN-alpha) prevents in vivo oncogenesis in very-early-stage cancer cells, we evaluated the action of IFN-alpha2b over preneoplastic foci in rats. Animals were divided into 6 groups: subjected to a 2-phase model (diethylnitrosamine [DEN] plus 2-acetylaminofluorene [2-AAF]) of preneoplasia development (group 1), treated with IFN-alpha2b during the 2 phases (group 2), only during initiation with DEN (group 3), only during administration of 2-AAF (group 4), subjected only to an initiation stage (group 5), and treated with IFN-alpha2b during this period (group 6). The numbers of placental form of rat glutathione S-transferase (rGST-P)-positive foci per liver and the foci as percentage of liver were significantly reduced in groups 2, 3, and 6 but not in group 4. Rats treated with IFN-alpha2b showed a higher apoptotic index (AI) in altered hepatic foci (AHF). Levels of p53 and Bax protein in liver lysates were significantly increased in those animals. Similarly, levels of antiapoptotic proteins Bcl-2 and Bcl-x(L) in mitochondrial fraction were decreased. Finally, increased levels of Bax protein were localized in the mitochondria of rats that received IFN-alpha2b, at least during the DEN phase (groups 2, 3, and 6), whereas mitochondrial Bax expression was not increased in group 4. In conclusion, the preneoplastic hepatocytes in rats that received IFN-alpha2b during the initiation stage undergo programmed cell death as a primary result of a significant increase in the amount and translocation to the mitochondria of Bax protein.
de Luján Alvarez
María
M
Instituto de Fisiología Experimental (IFISE-CONICET) and Area de Morfología, Facultad de Ciencias Bioquímicas y Farmacéuticas (UNR), Rosario, Argentina.
Cerliani
Juan Pablo
JP
Monti
Juan
J
Carnovale
Cristina
C
Ronco
María Teresa
MT
Pisani
Gerardo
G
Lugano
María Cristina
MC
Carrillo
María Cristina
MC
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000502:physiology*; D015153:Blotting, Western; D005982:Glutathione Transferase / Q000378:metabolism; D000077190:Interferon alpha-2; D016898:Interferon-alpha / Q000494:pharmacology*; D008099:Liver / Q000201:enzymology / Q000473:pathology; D008113:Liver Neoplasms / Q000503:physiopathology*; D008297:Male; D011230:Precancerous Conditions / Q000503:physiopathology*; D011518:Proto-Oncogene Proteins / Q000502:physiology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D011994:Recombinant Proteins; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D051028:bcl-2-Associated X Protein; D051020:bcl-X Protein
D000970:Antineoplastic Agents; C494828:Bax protein, rat; C494813:Bcl2l1 protein, rat; D000077190:Interferon alpha-2; D016898:Interferon-alpha; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D011994:Recombinant Proteins; D016159:Tumor Suppressor Protein p53; D051028:bcl-2-Associated X Protein; D051020:bcl-X Protein; D005982:Glutathione Transferase