The HPV-16 E7 oncogene sensitizes malignant cells to IFN-alpha-induced apoptosis.
Interferons (IFNs) exert antitumor effects in several human malignancies, but their mechanism of action is unclear. There is a great variability in sensitivity to IFN treatment depending on both tumor type and the individual patient. The reason for this variable sensitivity is not known. The fact that several IFN-induced anticellular effects are exerted through modulation of proto-oncogenes and tumor suppressor genes may indicate that the malignant genotype may be decisive in the cell's sensitivity to IFN. To determine if a deregulated oncogene could alter the cellular response to IFN, a mouse lymphoma cell line (J3D) was stably transfected with the viral human papillomavirus-16 (HPV-16) E7 oncogene. The E7-transfected cells and their respective mock-transfected sister clones were treated with IFN-alpha and examined for possible IFN-induced anticellular effects. We found that the E7-transfected clones were greatly sensitized to IFN-alpha-induced apoptosis compared with their mock-transfected counterparts. Induction of apoptosis in the transfected cells correlated with the ability of IFN to activate parts of the proapoptotic machinery specifically in these cells, including activation of caspases and the proapoptotic protein Bak. In summary, our data suggest that transfection of malignant cells with the E7 oncogene can sensitize them to IFN-alpha-induced apoptosis. This demonstrates that an oncogenic event may alter the cellular sensitivity to IFN and might also have implications for treatment of HPV-related diseases with IFN.
Thyrell
Lena
L
Department of Oncology and Pathology, Cancer Center Karolinska (CCK), Karolinska Hospital and Institute, S-171 76 Stockholm, Sweden.
Sangfelt
Olle
O
Zhivotovsky
Boris
B
Pokrovskaja
Katja
K
Wang
Yisong
Y
Einhorn
Stefan
S
Grandér
Dan
D
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D020169:Caspases / Q000378:metabolism; D002461:Cell Line, Transformed; D045744:Cell Line, Tumor; D002472:Cell Transformation, Viral; D004789:Enzyme Activation / Q000187:drug effects; D005434:Flow Cytometry; D016898:Interferon-alpha / Q000494:pharmacology*; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D009856:Oncogene Proteins, Viral / Q000235:genetics / Q000378:metabolism*; D027383:Papillomaviridae; D050725:Papillomavirus E7 Proteins; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D012190:Retroviridae / Q000235:genetics; D014162:Transfection; D050998:bcl-2 Homologous Antagonist-Killer Protein
C494773:Bak1 protein, mouse; D016898:Interferon-alpha; D008565:Membrane Proteins; D009856:Oncogene Proteins, Viral; D050725:Papillomavirus E7 Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D050998:bcl-2 Homologous Antagonist-Killer Protein; C059731:oncogene protein E7, Human papillomavirus type 16; D020169:Caspases