title: Caspase-8 mutations in head and neck cancer confer resistance to death receptor-mediated apoptosis and enhance migration, invasion, and tumor growth.
abstract: Little is known regarding molecular markers in head and neck squamous cell carcinoma (HNSCC) that predict responsiveness to different therapeutic regimens or predict HNSCC progression. Mutations in procaspase-8 occur in 9% of HNSCC primary tumors, but the functional consequences of these mutations are poorly understood. In this study, we examined the impact of four, representative, HNSCC-associated procaspase-8 mutations on activation of the extrinsic apoptosis pathway, as well as cellular migration and invasion, and in vivo tumor growth. All four mutant proteins acted to potently inhibit activation of apoptosis following treatment with TRAIL or agonistic anti-Fas. In contrast to wild-type procaspase-8, the mutant proteins were not recruited to FADD following treatment with TRAIL or anti-Fas, but may be constitutively bound by FADD. Three of the four procaspase-8 mutants promoted enhanced cellular migration and invasion through matrigel, relative to that seen with the wild-type procaspase-8 protein. Procaspase-8 mutation also stimulated the growth of HNSCC xenograft tumors. These findings indicate that HNSCC-associated procaspase-8 mutations inhibit activation of the extrinsic apoptosis pathway and are likely to represent markers for resistance to therapeutic regimens incorporating death receptor activators. Moreover, procaspase-8 mutations may serve as markers of HNSCC tumor progression, as exemplified by enhanced migration, invasion, and tumor growth.
authors.affiliation: Department of Medicine, University of Pittsburgh, University of Pittsburgh Cancer Institute, Pittsburgh, PA 15213, USA.
authors.forename: Changyou
authors.initials: C
authors.lastname: Li
authors.affiliation: Department of Otolaryngology, University of Pittsburgh, University of Pittsburgh Cancer Institute, Pittsburgh, PA 15213, USA.
authors.forename: Ann Marie
authors.initials: AM
authors.lastname: Egloff
authors.affiliation: Department of Otolaryngology, University of Pittsburgh, University of Pittsburgh Cancer Institute, Pittsburgh, PA 15213, USA.
authors.forename: Malabika
authors.initials: M
authors.lastname: Sen
authors.affiliation: Department of Otolaryngology, University of Pittsburgh, University of Pittsburgh Cancer Institute, Pittsburgh, PA 15213, USA; Department of Pharmacology & Chemical Biology, University of Pittsburgh, University of Pittsburgh Cancer Institute, Pittsburgh, PA 15213, USA.
authors.forename: Jennifer R
authors.initials: JR
authors.lastname: Grandis
authors.affiliation: Department of Medicine, University of Pittsburgh, University of Pittsburgh Cancer Institute, Pittsburgh, PA 15213, USA; Department of Pharmacology & Chemical Biology, University of Pittsburgh, University of Pittsburgh Cancer Institute, Pittsburgh, PA 15213, USA. Electronic address: johnsond@pitt.edu.
authors.forename: Daniel E
authors.initials: DE
authors.lastname: Johnson
mesh_terms: D000818:Animals; D017209:Apoptosis; D002294:Carcinoma, Squamous Cell / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D053181:Caspase 8 / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D002465:Cell Movement; D005260:Female; D006258:Head and Neck Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D008819:Mice, Nude; D009154:Mutation; D009361:Neoplasm Invasiveness / Q000235:genetics / Q000473:pathology; D053218:Receptors, Death Domain / Q000378:metabolism*; D000077195:Squamous Cell Carcinoma of Head and Neck
chemical_list: D053218:Receptors, Death Domain; D053181:Caspase 8
keywords: Caspase-8; Extrinsic apoptosis; HNSCC; Invasion; Migration