title: Caspase-8 expression and its Src-dependent phosphorylation on Tyr380 promote cancer cell neoplastic transformation and resistance to anoikis.
abstract: Caspase-8 expression is lost in a small percentage of tumors suggesting that the retention of its functionality may positively contribute to tumor progression. Consistently, several non-apoptotic functions of Caspase-8 have been identified and Caspase-8 has been shown to modulate cell adhesion, migration and to promote tumor progression. We have previously identified the Src-dependent phosphorylation of Caspase-8 on Tyr380 as a molecular mechanism to downregulate the proapoptotic function of Caspase-8; this phosphorylation occurs in colon cancer and may promote cell migration in neuroblastoma cell lines. However, the occurrence of Caspase-8 phosphorylation on Tyr380 and its significance in different carcinoma cellular models, have not been clarified yet. Here we show that Caspase-8 expression may promote cell transformation in glioblastoma and in hepatocarcinoma cell lines. In these systems Caspase-8 is phosphorylated on Tyr380 in a Src kinase dependent manner and this phosphorylation is required for transformation and it is enhanced by hypoxic conditions. Using a cancer cellular model characterized by Src constitutive activation engineered to express either Caspase-8-wt or Caspase-8-Y380F we could show that Caspase-8 expression and its phosphorylation on Tyr380, but not its enzymatic activity, promote in vitro cell transformation and resistance to anoikis. This work demonstrates a dual role for Caspase-8 in cancer, suggesting that Tyr380 phosphorylation may represent a molecular switch to hijack its activity from tumor suppressor to tumor promoter.
authors.affiliation: Department of Biology, University of Rome "Tor Vergata", 00133 Rome, Italy; Laboratory of Cell Signaling, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Fondazione Santa Lucia, 00179 Rome, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Fianco
authors.affiliation: Laboratory of Cell Signaling, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Fondazione Santa Lucia, 00179 Rome, Italy.
authors.forename: C
authors.initials: C
authors.lastname: Cenci
authors.affiliation: Department of Biology, University of Rome "Tor Vergata", 00133 Rome, Italy; Laboratory of Cell Signaling, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Fondazione Santa Lucia, 00179 Rome, Italy. Electronic address: daniela.barila@uniroma2.it.
authors.forename: D
authors.initials: D
authors.lastname: Barilà
mesh_terms: D023102:Anoikis; D017209:Apoptosis; D053181:Caspase 8 / Q000378:metabolism*; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000378:metabolism* / Q000473:pathology*; D003110:Colonic Neoplasms / Q000473:pathology; D004789:Enzyme Activation; D006801:Humans; D050505:Mutant Proteins / Q000378:metabolism; D010766:Phosphorylation; D019000:Phosphotyrosine / Q000378:metabolism*; D019061:src-Family Kinases / Q000378:metabolism*
chemical_list: D050505:Mutant Proteins; D019000:Phosphotyrosine; D019061:src-Family Kinases; D053181:Caspase 8
keywords: Anoikis; Caspase-8; Glioblastoma; Hepatocellular carcinoma; Hypoxia; Src kinase; Tyrosine phosphorylation