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

Oncogene volume 25, pages 2860–2872 (2006)Cite this article

A Correction to this article was published on 20 October 2022

A Correction to this article was published on 09 December 2019

This article has been updated

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.

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Acknowledgements

This work was supported by USPHS grants from the National Cancer Institure, P01 CA77738 (K Huebner) and P01 CA78890 (CM Croce), State of Pennsylvania Tobacco Settlement funds, funds from the Breast Cancer Program of US DOD, BC043090 (D Iliopoulos) and NIH training Grant T32-HLO7780 (KA McCorkell).

We thank Dr Shuang-Yin Han, for assistance in preparation of the recombinant adenoviral vectors, Drs Chang-Gong Liu and Xiuping Liu for assistance with microarray analysis, Drs Masaki Mori and Koshi Mimori for contribution of the esophageal cancer cell lines and Angela Robinson for expert assistance with preparation of purified Fhit proteins.

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Authors and Affiliations

  1. Comprehensive Cancer Center and Department of Molecular Virology, Immunology, and Medical Genetics, The Ohio State University, Columbus, OH, USA

    S Semba, F Trapasso, M Fabbri, K A McCorkell, S Volinia, T Druck, D Iliopoulos, Y Pekarsky, C M Croce & K Huebner

  2. Department of Experimental and Clinical Medicine, Medical School of Catanzaro, ‘Magna Graecia’ University of Catanzaro, Catanzaro, Italy

    F Trapasso

  3. Telethon Facility-Data Mining for Analysis of DNA Microarrays, Università degli Studi, Ferrara, Italy

    S Volinia

  4. Division of Stem Cell Regulation/Molecular Hematopoiesis, Center for Molecular Medicine, Jichi Medical School, Minami-Kawachi, Japan

    H Ishii

  5. Department of Biochemistry, University of Texas Health Science Center, San Antonio, TX, USA

    P N Garrison & L D Barnes

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  1. S Semba
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Correspondence to K Huebner.

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Supplementary information accompanies the paper on Oncogene website (http://www.nature.com/onc)

The original online version of this article was revised: The GFP blot images for Figure 1A, b, in this article have been removed because the original data are no longer available, thus these images cannot be validated.

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Semba, S., Trapasso, F., Fabbri, M. et al. Fhit modulation of the Akt-survivin pathway in lung cancer cells: Fhit-tyrosine 114 (Y114) is essential. Oncogene 25, 2860–2872 (2006). https://doi.org/10.1038/sj.onc.1209323

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