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Molecular and Cellular Biology, October 2005, p. 8809-8823, Vol. 25, No. 20
0270-7306/05/$08.00+0     doi:10.1128/MCB.25.20.8809-8823.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

mTOR Controls FLIPS Translation and TRAIL Sensitivity in Glioblastoma Multiforme Cells

Amith Panner,1 C. David James,2 Mitchel S. Berger,1 and Russell O. Pieper1*

Brain Tumor Research Center, Department of Neurological Surgery and University of California San Francisco Comprehensive Cancer Center, University of California San Francisco, San Francisco, California 94143-0875,1 Department of Laboratory Medicine and Pathology, Division of Experimental Pathology, Mayo Clinic, Rochester, Minnesota 559052

Received 20 April 2005/ Returned for modification 3 June 2005/ Accepted 11 July 2005

The tumor-selective, proapoptotic, death receptor ligand tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a mediator of antitumor drug activity and in itself is a promising agent for the treatment of human malignancies. Like many tumors, however, glioblastoma multiforme (GBM), the most fatal form of glioma, exhibits a range of TRAIL sensitivity, and only a small percentage of GBM tumors undergo TRAIL-induced apoptosis. We here show that TRAIL resistance in GBM is a consequence of overexpression of the short isoform of the caspase-8 inhibitor, c-FLICE inhibitory protein (FLIPS), and that FLIPS expression is in turn translationally enhanced by activation of the Akt-mammalian target of rapamycin (mTOR)-p70 S6 kinase 1 (S6K1) pathway. Conversely, pharmacologic or genetic inhibition of mTOR, or the mTOR target S6K1, suppresses polyribosomal accumulation of FLIPS mRNA, FLIPS protein expression, and TRAIL resistance. In archived material from 12 human GBM tumors, PTEN status was a predictor of activation of the Akt-mTOR-S6K1 pathway and of FLIPS levels, while in xenografted human GBM, activation status of the PTEN-Akt-mTOR pathway distinguished the tumors inherently sensitive to TRAIL from those which could be sensitized by the mTOR inhibitor rapamycin. These results define the mTOR pathway as a key limiter of tumor elimination by TRAIL-mediated mechanisms, provide a means by which the TRAIL-sensitive subset of GBM can be identified, and provide rationale for the combined use of TRAIL with mTOR inhibitors in the treatment of human cancers.

* Corresponding author. Mailing address: Department of Neurological Surgery, University of California San Francisco, 2340 Sutter Street, Room N261, Box 0875, San Francisco, CA 94115. Phone: (415) 502-7132. Fax: (415) 502-6779. E-mail: rpieper{at}cc.ucsf.edu.

Molecular and Cellular Biology, October 2005, p. 8809-8823, Vol. 25, No. 20
0022-538X/05/$08.00+0     doi:10.1128/MCB.25.20.8809-8823.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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