Triggering of death receptor apoptotic signaling by human papillomavirus 16 E2 protein in cervical cancer cell lines is mediated by interaction with c-FLIP.

Abstract

Human papillomavirus (HPV) E2 gene disruption is one of the key features of HPV-induced cervical malignant transformation. Though it is thought to prevent progression of carcinogenesis, the pro-apoptotic function of E2 protein remains poorly understood. This study shows that expression of HPV16 E2 induces apoptosis both in HPV-positive and -negative cervical cancer cell lines and leads to hyperactivation of caspase-8 and caspase-3. Activation of these signaling factors is responsible for the observed sensitivity to apoptosis upon treatment with anti-Fas antibody or TNF-α. In addition, immunoprecipitation experiments clearly show an interaction between HPV16 E2 and c-FLIP, a key regulator of apoptotic cell death mediated by death receptor signaling. Moreover, c-FLIP and a caspase-8 inhibitor protect cells from HPV16 E2-mediated apoptosis. Overexpression of c-FLIP rescues cervical cancer cells from apoptosis induced by HPV16 E2 protein expression. The data suggest that HPV16 E2 abrogates the apoptosis-inhibitory function of c-FLIP and renders the cell hypersensitive to the Fas/FasL apoptotic signal even below threshold concentration. This suggests a novel mechanism for deregulation of cervical epithelial cell growth upon HPV-induced transformation, which is of great significance in developing therapeutic strategies for intervention of cervical carcinogenesis.

• Authors: Wei Wang, Yong Fang, Ni Sima, Yan Li, Wei Li, Li Li, Linfei Han, Shujie Liao, Zhiqiang Han, Qinglei Gao, Kezhen Li, Dongrui Deng, Li Meng, Jianfeng Zhou, Shixuan Wang, Ding Ma
• Journal: Apoptosis : an international journal on programmed cell death (Apoptosis) Vol. 16 Issue 1 Pg. 55-66 (Jan 2011) ISSN: 1573-675X [Electronic] Netherlands
• PMID: 20882347 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antibodies, Monoclonal
• Antibodies, Monoclonal, Murine-Derived
• Apoptosis Regulatory Proteins
• CASP8 and FADD-Like Apoptosis Regulating Protein
• DNA-Binding Proteins
• FAIM protein, human
• Oncogene Proteins, Viral
• Receptors, Death Domain
• TNF-Related Apoptosis-Inducing Ligand
• Tumor Necrosis Factor-alpha
• anti-Fas monoclonal antibody
• oncogene protein E2, Human papillomavirus type 1
• Caspase 3
• Caspase 8

Topics

• Antibodies, Monoclonal (pharmacology)
• Antibodies, Monoclonal, Murine-Derived
• Apoptosis (drug effects)
• Apoptosis Regulatory Proteins
• CASP8 and FADD-Like Apoptosis Regulating Protein (genetics, metabolism)
• Caspase 3 (genetics, metabolism)
• Caspase 8 (genetics, metabolism)
• Cell Line, Tumor
• DNA-Binding Proteins (genetics, metabolism)
• Female
• Gene Expression (drug effects)
• Humans
• Oncogene Proteins, Viral (genetics, metabolism)
• Papillomaviridae (genetics, metabolism)
• Receptors, Death Domain (metabolism)
• Signal Transduction (drug effects)
• TNF-Related Apoptosis-Inducing Ligand (metabolism)
• Tumor Necrosis Factor-alpha (pharmacology)
• Up-Regulation
• Uterine Cervical Neoplasms (genetics, metabolism, virology)