TY - JOUR
T1 - Efficacy of TRAIL treatment against HPV16 infected cervical cancer cells undergoing senescence following siRNA knockdown of E6/E7 genes
AU - Eaton, Seron
AU - Wiktor, Peter
AU - Thirstrup, Derek
AU - Lake, Douglas
AU - Nagaraj, Vinay Janthakahalli
N1 - Funding Information:
Jaminson Rupnik, Ian Blong and Erica Arroyo for technical help. The Biodesign Institute at Arizona State University for financial support.
Copyright:
Copyright 2011 Elsevier B.V., All rights reserved.
PY - 2011/2/4
Y1 - 2011/2/4
N2 - In this study we investigated E6 and E7 oncogenes from the Human Papilloma Virus as targets for siRNA knockdown in order to boost the efficacy of the anti-cancer drug 'tumor necrosis factor-related apoptosis inducing ligand' (TRAIL). SiHa cells were treated with TRAIL following transfection with E6/E7 siRNA and the expression of death receptors DR4 and DR5, cell viability, apoptosis, senescence and cell cycle analysis were undertaken using flow cytometry, MTT viability assay and cellular β-galactosidase activity assays. E6/E7 siRNA resulted in significant upregulation of death receptors DR4 and DR5 but did not result in an enhanced sensitivity to TRAIL. Our results indicate that E6/E7-siRNA induces senescence rather than apoptosis in SiHa cells. The occurrence of senescence in drug resistant cervical cancer cells such as the SiHa cell line by E6/E7 siRNA, among other factors, may prevent TRAIL induced activation of extrinsic and intrinsic pathways that lead to apoptotic cell death. Our findings are significant for combinatorial strategies for cancer therapy since the induction of senescence can preclude apoptosis rendering cells to be recalcitrant to TRAIL treatment.
AB - In this study we investigated E6 and E7 oncogenes from the Human Papilloma Virus as targets for siRNA knockdown in order to boost the efficacy of the anti-cancer drug 'tumor necrosis factor-related apoptosis inducing ligand' (TRAIL). SiHa cells were treated with TRAIL following transfection with E6/E7 siRNA and the expression of death receptors DR4 and DR5, cell viability, apoptosis, senescence and cell cycle analysis were undertaken using flow cytometry, MTT viability assay and cellular β-galactosidase activity assays. E6/E7 siRNA resulted in significant upregulation of death receptors DR4 and DR5 but did not result in an enhanced sensitivity to TRAIL. Our results indicate that E6/E7-siRNA induces senescence rather than apoptosis in SiHa cells. The occurrence of senescence in drug resistant cervical cancer cells such as the SiHa cell line by E6/E7 siRNA, among other factors, may prevent TRAIL induced activation of extrinsic and intrinsic pathways that lead to apoptotic cell death. Our findings are significant for combinatorial strategies for cancer therapy since the induction of senescence can preclude apoptosis rendering cells to be recalcitrant to TRAIL treatment.
KW - Apoptosis
KW - Combinatorial cancer treatment
KW - Drug-resistant cervical cancer
KW - Senescence
KW - SiRNA therapy
KW - Tumor necrosis factor-related apoptosis inducing ligand (TRAIL)
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U2 - 10.1016/j.bbrc.2010.12.056
DO - 10.1016/j.bbrc.2010.12.056
M3 - Article
C2 - 21167816
AN - SCOPUS:79551496194
SN - 0006-291X
VL - 405
SP - 1
EP - 6
JO - Biochemical and Biophysical Research Communications
JF - Biochemical and Biophysical Research Communications
IS - 1
ER -