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.

Fianco, G., Cenci, C., Barila', D. (2016). Caspase-8 expression and its Src-dependent phosphorylation on Tyr380 promote cancer cell neoplastic transformation and resistance to anoikis. EXPERIMENTAL CELL RESEARCH, 347(1), 114-122 [10.1016/j.yexcr.2016.07.013].

Caspase-8 expression and its Src-dependent phosphorylation on Tyr380 promote cancer cell neoplastic transformation and resistance to anoikis

FIANCO, GIULIA;BARILA', DANIELA
2016-09-10

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.
10-set-2016
Pubblicato
Rilevanza internazionale
Articolo
Esperti anonimi
Settore BIO/18 - GENETICA
English
Anoikis; Caspase-8; Glioblastoma; Hepatocellular carcinoma; Hypoxia; Src kinase; Tyrosine phosphorylation
https://www.sciencedirect.com/science/article/abs/pii/S0014482716301926?via=ihub
Fianco, G., Cenci, C., Barila', D. (2016). Caspase-8 expression and its Src-dependent phosphorylation on Tyr380 promote cancer cell neoplastic transformation and resistance to anoikis. EXPERIMENTAL CELL RESEARCH, 347(1), 114-122 [10.1016/j.yexcr.2016.07.013].
Fianco, G; Cenci, C; Barila', D
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2108/173573
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