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

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.

• Authors: 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
• Journal: Oncogene (Oncogene) Vol. 25 Issue 20 Pg. 2860-72 (May 11 2006) ISSN: 0950-9232 [Print] England
• PMID: 16407838 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• BIRC5 protein, human
• Inhibitor of Apoptosis Proteins
• Microtubule-Associated Proteins
• Neoplasm Proteins
• RNA, Small Interfering
• Survivin
• fragile histidine triad protein
• Tyrosine
• Phosphatidylinositol 3-Kinases
• Class I Phosphatidylinositol 3-Kinases
• PIK3CA protein, human
• Proto-Oncogene Proteins c-akt
• Acid Anhydride Hydrolases

Topics

• Acid Anhydride Hydrolases (genetics)
• Adenoviridae (genetics)
• Blotting, Western
• Class I Phosphatidylinositol 3-Kinases
• Flow Cytometry
• Gene Expression Profiling
• Gene Expression Regulation (physiology)
• Genes, Tumor Suppressor (physiology)
• Humans
• Inhibitor of Apoptosis Proteins
• Lung Neoplasms (genetics, metabolism)
• Microtubule-Associated Proteins (genetics, metabolism)
• Neoplasm Proteins (genetics, metabolism)
• Oligonucleotide Array Sequence Analysis
• Phosphatidylinositol 3-Kinases (genetics, metabolism)
• Proto-Oncogene Proteins c-akt (genetics, metabolism)
• RNA, Small Interfering (pharmacology)
• Reverse Transcriptase Polymerase Chain Reaction
• Signal Transduction
• Survivin
• Tumor Cells, Cultured
• Tyrosine (genetics, metabolism)