Carcinoma cell lines become sensitive to DNA-damaging agents by the expression of the adenovirus E1A gene.
Squamous cell carcinomas can show different oncogenic alterations, histological patterns, and an unpredictable clinical behavior. We previously reported that the adenovirus E1a gene may induce sensitivity to DNA-damaging agents in mouse keratinocytes. In order to study whether E1a expression could be used as a therapeutic agent in different malignant cell lines carrying mutations on the p53 gene and other oncogenic alterations, we transfected and infected several murine and human carcinoma cell lines (HaCa4; MSC11A5; HeLa) with vectors containing the 13S or 12S E1a region. We evaluated the sensitivity to cisplatin (CDDP), doxorubicin (DOX) and gamma irradiation (RX) by the crystal violet method. The induction of apoptosis was assessed by flow cytometry and presence of DNA ladders in agarose gels. The expression of E1a and the tumor suppressor p53 protein was analysed by Western blotting. The carcinoma cell lines expressing E1a were about four- to tenfold more sensitive to CDDP and RX, respectively, than the control cells. Moreover, the reduction in cell viability and cell growth after exposure to CDDP or RX was very significant in the carcinoma cells expressing E1a. With these results, we conclude that expression of E1a may confer great sensitivity to DNA-damaging agents on squamous cell carcinoma cells independently of the p53 protein status and other oncogenic alterations.
Sánchez-Prieto
R
R
Dpto. Patologia, Clinica Puerta de Hierro, San Martin de Porres, Madrid, Spain.
Quintanilla
M
M
Cano
A
A
Leonart
M L
ML
Martin
P
P
Anaya
A
A
Ramón y Cajal
S
S
D000256:Adenoviridae / Q000472:pathogenicity; D017500:Adenovirus E1A Proteins / Q000187:drug effects / Q000235:genetics*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics / Q000528:radiation effects; D002277:Carcinoma / Q000235:genetics* / Q000473:pathology / Q000628:therapy*; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D002455:Cell Division / Q000187:drug effects / Q000235:genetics / Q000528:radiation effects; D002945:Cisplatin / Q000494:pharmacology; D004249:DNA Damage / Q000187:drug effects* / Q000528:radiation effects; D004317:Doxorubicin / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005720:Gamma Rays; D006367:HeLa Cells / Q000187:drug effects; D006801:Humans; D051379:Mice; D009154:Mutation; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology; D014162:Transfection; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis / Q000187:drug effects / Q000235:genetics
D017500:Adenovirus E1A Proteins; D000970:Antineoplastic Agents; D011838:Radiation-Sensitizing Agents; D016159:Tumor Suppressor Protein p53; D004317:Doxorubicin; D002945:Cisplatin