Fhit modulation of the Akt-survivin pathway in lung cancer cells: Fhit-tyrosine 114 (Y114) is essential

S. Semba, F. Trapasso, M. Fabbri, K. A. McCorkell, S. Volinia, T. Druck, D. Iliopoulos, Y. Pekarsky, H. Ishii, P. N. Garrison, L. D. Barnes, C. M. Croce, K. Huebner

Research output: Contribution to journalArticlepeer-review

60 Scopus citations

Abstract

The Fhit tumor suppressor binds and hydrolyses diadenosine polyphosphates and the Fhit-substrate complex has been proposed as a proapoptotic effector, as determined by infection of susceptible cancer cells with adenoviruses carrying wild-type fragile histidine triad (FHIT) or catalytic site mutants. The highly conserved Fhit tyrosine 114 (Y114), within the unstructured loop C-terminal of the catalytic site, can be phosphorylated by Src family tyrosine kinases, although endogenous phospho-Fhit is rarely detected. To explore the importance of Y114 and identify Fhit-mediated signaling events, wild-type and Y114 mutant FHIT-expressing adenoviruses were introduced into two human lung cancer cell lines. Caspase-dependent apoptosis was effectively induced only by wild-type but not Y114 mutant Fhit proteins. By expression profiling of FHIT versus mutant FHIT-infected cells, we found that survivin, an Inhibitor of Apoptosis Protein (IAP) family member, was significantly decreased by wild-type Fhit. In addition, Fhit inhibited activity of Akt, a key effector in the phosphatidylinositol 3-OH kinase (PI3K) pathway; loss of endogenous Fhit expression caused increased Akt activity in vitro and in vivo, and overexpression of constitutively active Akt inhibited Fhit-induced apoptosis. The results indicate that the Fhit Y114 residue plays a critical role in Fhit-induced apoptosis, occurring through inactivation of the PI3K-Akt-survivin signal pathway.

Original languageEnglish (US)
Pages (from-to)2860-2872
Number of pages13
JournalOncogene
Volume25
Issue number20
DOIs
StatePublished - May 11 2006

Keywords

  • Akt
  • Apoptosis
  • Fhit
  • Lung cancer
  • Survivin
  • Tyrosine 114 (Y114)

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

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