The PTEN/Akt pathway dictates the direct αvβ 3-dependent growth-inhibitory action of an active fragment of tumstatin in glioma cells in vitro and in vivo

Tomohiro Kawaguchi, Yoji Yamashita, Masayuki Kanamori, Raelene Endersby, Krystof S. Bankiewicz, Suzanne J. Baker, Gabriele Bergers, Russell O. Pieper

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45 Citations (Scopus)


The collagen type IV cleavage fragment tumstatin and its active subfragments bind to integrin αvβ3 and inhibit activation of focal adhesion kinase, phophoinositol-3 kinase, Akt, and mammalian target of rapamycin (mTOR) in what is thought to be an endothelial cell-specific manner. The resultant endothelial cell apoptosis accounts for the ability of tumstatin to function as an endogenous inhibitor of angiogenesis and an indirect suppressor of tumor growth. We hypothesized that the inability of tumstatin to directly suppress tumor cell growth might be the result of the constitutive activation of the Akt/mTOR pathway commonly seen in tumors. Consistent with this idea, several integrin αvβ 3-expressing glioma cell lines with PTEN mutations and high levels of phospho-Akt (pAkt) were unaffected by exposure to an active fragment of tumstatin (T3), whereas αvβ3-expressing glioma cell lines with a functional PTEN/low levels of pAkt exhibited T3-induced growth suppression that could be bypassed by small interfering RNA-mediated suppression of PTEN, introduction of a constitutively expressed Akt, or introduction of the Akt and mTOR target eukaryotic translation initiation factor 4E. The direct tumor-suppressive actions of T3 were further shown in an αvβ3-deficient in vivo mouse model in which T3, while unable to alter the tumstatin-insensitive vasculature contributed by the αvβ3-deficient host, nonetheless suppressed the growth and proliferative index of i.e. implanted αvβ 3-expressing PTEN-proficient glioma cells. These results show that tumstatin, previously considered to be only an endogenous inhibitor of angiogenesis, also directly inhibits the growth of tumors in a manner dependent on Akt/mTOR activation.

Original languageEnglish
Pages (from-to)11331-11340
Number of pages10
JournalCancer Research
Issue number23
Publication statusPublished - 2006 Dec 1

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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