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

Apoptosis. 2011 Jan;16(1):55-66. doi: 10.1007/s10495-010-0543-3.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antibodies, Monoclonal / pharmacology
  • Antibodies, Monoclonal, Murine-Derived
  • Apoptosis / drug effects*
  • Apoptosis Regulatory Proteins
  • CASP8 and FADD-Like Apoptosis Regulating Protein / genetics
  • CASP8 and FADD-Like Apoptosis Regulating Protein / metabolism*
  • Caspase 3 / genetics
  • Caspase 3 / metabolism*
  • Caspase 8 / genetics
  • Caspase 8 / metabolism*
  • Cell Line, Tumor
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism*
  • Female
  • Gene Expression / drug effects
  • Humans
  • Oncogene Proteins, Viral / genetics
  • Oncogene Proteins, Viral / metabolism*
  • Papillomaviridae / genetics
  • Papillomaviridae / 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
  • Uterine Cervical Neoplasms / metabolism
  • Uterine Cervical Neoplasms / virology

Substances

  • 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