Adenoviral delivery of VHL suppresses bone sarcoma cell growth through inhibition of Wnt/β-catenin signaling

Cancer Gene Therapy
Changbao ChenXinlong Ma

Abstract

The VHL tumor suppressor gene is frequently inactivated in several human tumors, including bone sarcomas. We previously identified that reduced expression of VHL protein is implicated in sarcomagenesis. However, the underlying biological functions of restored VHL protein expression have not been clearly elucidated in bone sarcomas. Here we initially constructed a recombinant adenovirus 5-VHL vector (Ad5-VHL) and evaluated its expression in bone sarcomas, and antitumor activity in vitro and in vivo. We found that the adenovirus-mediated increase of VHL significantly suppresses bone sarcoma cell growth, attributed to induction of apoptosis mediated by increased caspase-3 activity and modulated Bcl-2 protein family. This suppression effect involves inhibition of Wnt/β-catenin signaling and upregulation of GSK-3β. Moreover, Ad5-VHL showed a dramatic antitumor effect on a chondrosarcoma xenograft model. These findings establish that Ad5-VHL suppresses bone sarcoma cell growth by inhibiting Wnt/β-catenin signaling, and may be a novel target for gene-based therapy of bone sarcomas.

References

Aug 22, 2001·The Journal of Biological Chemistry·P DevarajanR D Burk
Aug 31, 2001·Progress in Neurobiology·C A Grimes, R S Jope
Mar 21, 2002·Nature Reviews. Cancer·Adrian L Harris
Jan 3, 2003·Nature Cell Biology·Alexander HergovichWilhelm Krek
Sep 17, 2004·Nature Reviews. Genetics·Randall T MoonAjamete Kaykas
May 9, 2006·Molecular Cell·Jae-Seok RoeHong-Duk Youn
Jul 19, 2006·Molecular and Cellular Biology·Alexander HergovichWilhelm Krek
Sep 20, 2006·Proceedings of the National Academy of Sciences of the United States of America·Benedetta PeruzziDonald P Bottaro
Jan 16, 2007·Nature Cell Biology·Abderrahmane KaidiChristos Paraskeva
Jan 24, 2007·The International Journal of Biochemistry & Cell Biology·Dionysios J Papachristou, Athanasios G Papavassiliou
Nov 3, 2007·Mayo Clinic Proceedings·Keith M Skubitz, David R D'Adamo
Jul 12, 2008·Nature Reviews. Immunology·Frank J T StaalMachteld M Tiemessen
Oct 28, 2008·The International Journal of Biochemistry & Cell Biology·W Marston LinehanDonald P Bottaro
Feb 17, 2009·Trends in Biochemical Sciences·Jason D BerndtMichael B Major
Jul 22, 2009·Developmental Cell·Bryan T MacDonaldXi He
Mar 30, 2010·Apoptosis : an International Journal on Programmed Cell Death·Changbao ChenYingyu Chen
Mar 8, 2011·Cell·Douglas Hanahan, Robert A Weinberg
Apr 23, 2011·Expert Opinion on Investigational Drugs·Jessica Lee Yarber, Mark Agulnik
Oct 19, 2011·The Journal of Bone and Joint Surgery. American Volume·Changbao ChenQingjun Ma
Dec 18, 2013·Biochemical and Biophysical Research Communications·Dong-dong ChengQing-cheng Yang
Dec 24, 2014·Nature Reviews. Cancer·Lucy GossageEamonn R Maher

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Citations

Sep 4, 2019·Molecular Carcinogenesis·Changbao ChenXinlong Ma
Jun 12, 2021·OncoTargets and Therapy·Changbao ChenXinlong Ma
Jul 1, 2021·Cancer Management and Research·Changbao ChenXinlong Ma

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Methods Mentioned

BETA
ubiquitination
density gradient centrifugation
transfection
PCR
Assay
xenograft
flow cytometry
FACS
xenografts

Software Mentioned

SPSS
Cell Quest

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