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The PTEN/Akt Pathway Dictates the Direct _Vß₃-Dependent Growth-Inhibitory Action of an Active Fragment of Tumstatin in Glioma Cells In vitro and In vivo

¹ Brain Tumor Research Center, Department of Neurological Surgery and The University of California-San Francisco Comprehensive Cancer Center, University of California San Francisco, San Francisco, California and ² Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, Tennessee

Requests for reprints: Russell O. Pieper, Brain Tumor Research Center, Department of Neurological Surgery and The University of California-San Francisco Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA 94115-0875. Phone: 415-502-7132; Fax: 415-502-6779; E-mail: rpieper{at}cc.ucsf.edu.

The collagen type IV cleavage fragment tumstatin and its active subfragments bind to integrin _Vß₃ 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 _Vß₃–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 _Vß₃-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 _Vß₃-deficient in vivo mouse model in which T3, while unable to alter the tumstatin-insensitive vasculature contributed by the _Vß₃-deficient host, nonetheless suppressed the growth and proliferative index of i.c. implanted _Vß₃-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. (Cancer Res 2006; 66(23): 11331-40)

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