Mol
Cancer Res. 2006 Aug 2; [Epub ahead of print] Protein Expression Profiling Identifies Cyclophilin A as a Molecular Target in Fhit-Mediated Tumor Suppression. ·
Semba S, ·
Huebner K. Immunology, and Medical
Genetics, Loss of fragile histidine triad (Fhit)
expression is often associated with human malignancies, and Fhit functions as a tumor suppressor in controlling
cell growth and apoptosis, although specific signal pathways are still
undefined. We have used a proteomic approach to define proteins in the Fhit-mediated tumor suppression pathway. Because
substitution of Tyr(114) (Y114) with phenylalanine (Y114F) diminishes Fhit functions, we did protein expression profiling to
identify proteins differentially expressed in Fhit-negative
H1299 lung cancer cells infected with wild-type (Ad-FHIT-wt) and Y114
mutant FHIT-expressing (Ad-FHIT-Y114F) adenoviruses. Among 12 distinct
proteins that exhibited 4-fold differences in expression on comparison of
the two infected cell lysates, cyclophilin A, the intracellular reporter of the
immunosuppressive drug cyclosporine A, showed a remarkably decreased
protein level in cells infected with Ad-FHIT-wt versus Ad-FHIT-Y114F.
Conversely, loss of Fhit expression resulted in
increased cyclophilin A
expression in mouse tissues and cell lines. Restoration of Fhit expression led to down-regulated cyclophilin A protein expression and subsequently
prevented cyclophilin A-induced up-regulation of cyclin D1, Cdk4, and resultant cell cycle progression
(G1-S transition), which was independent of Ca(2+)/calmodulin-dependent
kinase inhibitor, KN-93. Interestingly, Fhit down-modulation of phosphatase
activity of calcineurin, which controls cyclin D1/Cdk4 activation, was reversed by cyclophilin A treatment in a
concentration-dependent manner, a reversal that was inhibited by additional
cyclosporine A treatment. Thus, cyclophilin A is
a downstream target in Fhit-mediated cessation of
cell cycle progression at late G1 phase. Elucidation of the protein
effectors of Fhit signaling may lead to
identification of targets for lung cancer therapy. (Mol Cancer Res 2006;4(8):1-10). PMID: 16885564 [PubMed
- as supplied by publisher]
Lung Cancer
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