title: Differential response of head and neck cancer cell lines to TRAIL or Smac mimetics is associated with the cellular levels and activity of caspase-8 and caspase-10.
abstract: BACKGROUND
  Current treatment strategies for head and neck cancer are associated with significant morbidity and up to 50% of patients relapse, highlighting the need for more specific and effective therapeutics. Tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) and Smac mimetics (SMs) are promising anticancer agents, but their effect on head and neck squamous cell carcinoma (HNSCC) remains unknown.
  
  
  METHODS
  We examined the response of a panel of nine HNSCC cell lines to TRAIL and SMs and investigated the mechanism of cell type-specific response by functional analysis.
  
  
  RESULTS
  Head and neck cancer cell lines revealed a converse response pattern with three cell lines being highly sensitive to Smac-164 (SM) but resistant to TRAIL, whereas the other six were sensitive to TRAIL but resistant to SM. Distinct protein expression and activation patterns were found to be associated with susceptibility of HNSCC cell lines to TRAIL and SM. Tumour necrosis factor-related apoptosis-inducing ligand sensitivity was associated with high caspase-8 and Bid protein levels, and TRAIL-sensitive cell lines were killed via the type II extrinsic apoptotic pathway. Smac mimetic-sensitive cells expressed low levels of caspase-8 and Bid but had high TNF-α expression. Smac mimetic-induced cell death was associated with caspase-10 activation, suggesting that in the absence of caspase-8, caspase-10 mediates response to SM. Cotreatment with TNF-α sensitised the resistant cells to SM, demonstrating a decisive role for TNF-α-driven feedback loop in SM sensitivity.
  
  
  CONCLUSIONS
  Tumour necrosis factor-related apoptosis-inducing ligand and SMs effectively kill HNSCC cell lines and therefore represent potential targeted therapeutics for head and neck cancer. Distinct molecular mechanisms determine the sensitivity to each agent, with levels of TNF-α, caspase-8, Bid and caspase-10 providing important predictive biomarkers of response to these agents.
authors.affiliation: Department of Molecular Oncology, King's College London, Guy's Hospital Campus, Hodgkin Building, London SE1 1UL, UK.
authors.forename: N
authors.initials: N
authors.lastname: Raulf
authors.affiliation: Department of Molecular Oncology, King's College London, Guy's Hospital Campus, Hodgkin Building, London SE1 1UL, UK.
authors.forename: R
authors.initials: R
authors.lastname: El-Attar
authors.affiliation: Experimental Dermatology, Department of Dermatology, TU-Dresden, Fetscherstrasse 74, 01307 Dresden, Germany.
authors.forename: D
authors.initials: D
authors.lastname: Kulms
authors.affiliation: Department of Experimental Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Amadeo 42, 20133 Milano, Italy.
authors.forename: D
authors.initials: D
authors.lastname: Lecis
authors.affiliation: Department of Experimental Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Amadeo 42, 20133 Milano, Italy.
authors.forename: D
authors.initials: D
authors.lastname: Delia
authors.affiliation: Centre for Cell Death, Cancer and Inflammation (CCCI) UCL Cancer Institute, 72 Huntley Street, London WC1E 6BT, UK.
authors.forename: H
authors.initials: H
authors.lastname: Walczak
authors.affiliation: Centre for Cell Death, Cancer and Inflammation (CCCI) UCL Cancer Institute, 72 Huntley Street, London WC1E 6BT, UK.
authors.forename: K
authors.initials: K
authors.lastname: Papenfuss
authors.affiliation: Department of Molecular Oncology, King's College London, Guy's Hospital Campus, Hodgkin Building, London SE1 1UL, UK.
authors.forename: E
authors.initials: E
authors.lastname: Odell
authors.affiliation: Department of Molecular Oncology, King's College London, Guy's Hospital Campus, Hodgkin Building, London SE1 1UL, UK.
authors.forename: M
authors.initials: M
authors.lastname: Tavassoli
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D051023:BH3 Interacting Domain Death Agonist Protein / Q000378:metabolism; D032701:Biomimetics; D015153:Blotting, Western; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology*; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D053455:Caspase 10 / Q000378:metabolism*; D053181:Caspase 8 / Q000378:metabolism*; D049109:Cell Proliferation / Q000187:drug effects; D004797:Enzyme-Linked Immunosorbent Assay; D006258:Head and Neck Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000494:pharmacology*; D014230:Triazoles / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D051023:BH3 Interacting Domain Death Agonist Protein; D019086:Bridged Bicyclo Compounds, Heterocyclic; C533467:SM 164; D053221:TNF-Related Apoptosis-Inducing Ligand; D014230:Triazoles; D014409:Tumor Necrosis Factor-alpha; D053455:Caspase 10; D053181:Caspase 8