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

Area of Science:

• Oncology
• Molecular Biology
• Cancer Research

Background:

• The fragile histidine triad (FHIT) protein acts as a tumor suppressor by binding and hydrolyzing diadenosine polyphosphates.
• The FHIT-substrate complex is implicated as a pro-apoptotic effector, influencing cancer cell death.
• Phosphorylation of FHIT at tyrosine 114 (Y114) by Src kinases is known, but its functional significance is unclear.

Purpose of the Study:

• To investigate the role of FHIT's Y114 residue in FHIT-mediated apoptosis.
• To identify signaling pathways regulated by FHIT, particularly in lung cancer.
• To elucidate the mechanism by which FHIT induces apoptosis.

Main Methods:

• Adenoviruses encoding wild-type FHIT or Y114 FHIT mutants were used to infect human lung cancer cell lines.
• Caspase-dependent apoptosis was assessed.
• Expression profiling was performed to identify differentially expressed genes.
• Activity of the PI3K-Akt pathway and survivin levels were analyzed.

Main Results:

• Wild-type FHIT induced caspase-dependent apoptosis, whereas the Y114 mutant did not.
• Wild-type FHIT significantly decreased survivin, an Inhibitor of Apoptosis Protein (IAP).
• FHIT inhibited the activity of the PI3K-Akt pathway; loss of FHIT increased Akt activity.
• Overexpression of active Akt suppressed FHIT-induced apoptosis.

Conclusions:

• The Y114 residue of FHIT is critical for its pro-apoptotic function.
• FHIT induces apoptosis by inactivating the PI3K-Akt-survivin signaling pathway.
• FHIT's tumor suppressor activity is mediated through the regulation of this critical survival pathway.