Down-regulation of multiple cell survival proteins in head and neck cancer cells by an apoptogenic mutant of adenovirus type 5.
Head and neck squamous cell carcinomas (HNSCC) are one of the leading causes of cancer deaths world wide. Up-regulation of the epidermal growth factor receptor (EGFR) and BCL-2 family anti-apoptosis proteins in these cancers is linked to aggressive tumor growth, metastasis and chemoresistance. Infection of two HNSCC cell lines, SCC25 and CAL27 by an Ad5 mutant (lp11w) defective in coding for the viral anti-apoptosis protein, E1B-19K efficiently induced apoptotic cell death. In cells infected with lp11w there was a dramatic down-regulation of EGFR by apoptosis-dependent and -independent mechanisms. The levels of the anti-apoptotic proteins BCL-2, BCL-xL and MCL-1 were also down-regulated in lp11w-infected cells compared to uninfected or Ad5-RM infected cells. Infection with lp11w also enhanced sensitivity of the HNSCC cells to the chemotherapeutic drug cisplatin. Our results suggest that adenoviral vectors defective in E1B-19K would be valuable for efficient down-regulation of cell survival proteins and EGFR in epithelial cancers and could be exploited as oncolytic agents to treat HNSCCs.
Vijayalingam
S
S
Institute for Molecular Virology, Saint Louis University School of Medicine, 1100 South Grand Blvd, St. Louis, MO 63104, USA.
Subramanian
T
T
Ryerse
Jan
J
Varvares
Mark
M
Chinnadurai
G
G
D000260:Adenoviruses, Human / Q000235:genetics* / Q000502:physiology*; D017209:Apoptosis; D001483:Base Sequence; D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000378:metabolism / Q000628:therapy; D045744:Cell Line, Tumor; D002470:Cell Survival; D004279:DNA, Viral / Q000235:genetics; D015536:Down-Regulation; D019008:Drug Resistance, Neoplasm; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism; D005822:Genetic Vectors; D006258:Head and Neck Neoplasms / Q000235:genetics* / Q000378:metabolism* / Q000628:therapy; D006801:Humans; D009154:Mutation; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D050130:Oncolytic Virotherapy; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics* / Q000378:metabolism*; D051020:bcl-X Protein / Q000235:genetics / Q000378:metabolism
C494811:BCL2L1 protein, human; D004279:DNA, Viral; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D019253:Proto-Oncogene Proteins c-bcl-2; D051020:bcl-X Protein; D066246:ErbB Receptors