Chemo-radio resistance in cervical cancer induced by HPV16 E7

Abstract

Alteration of the apoptosis pathway, as well as the presence of human papilloma virus (HPV), has been linked to the proliferative capacity and drug resistant phenotype of SiHa cervical cancer. We investigated the roles of E6 and E7 HPV oncoproteins in the expression of apoptosis regulating genes in cervical cancer cells that contain the characteristics of apoptosis resistance, and also their correlation with resistance to various apoptosis inducing agents. The expression of the sets of apoptosis regulating genes in both extrinsic (receptor) and intrinsic (non-receptor) pathways were monitored in parental SiHa and multi-drug resistant SiHa (SiHaR) cell lines by RNase protection assay and RT-PCR. An increase in gene expression of intrinsic pathway anti-apoptotic protein Bcl-XL was seen, both at the mRNA and protein levels, in SiHaR compared with SiHa cells, whereas the expression of the genes involved in the extrinsic pathway remained unchanged. SiHaR cells also expressed higher levels of E6 and E7 than did SiHa. Caspase 3 activity was lower in SiHaR compared with that in SiHa cells. A colony formation assay demonstrated enhanced resistance of SiHaR cells to several types of apoptosis inducing agents, including etoposide, doxorubicin, cisplatin, and γ-radiation. Transfection of HPV-negative C33a cells with HPV oncogenes, E7 in particular, induced transcription of Bcl-XL, supporting the role of HPV oncoproteins in affording chemo-radio resistance in cervical cancer.