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Decreased oxygen causes a rapid inhibition of mRNA translation. An important regulatory mechanism of translational repression under hypoxic conditions involves inhibition of the mammalian target of rapamycin (mTOR). mTOR is a target of the phosphatase and tensin homologue detected on chromosome 10 (PTEN)/phosphatidylinositol 3-kinase/AKT/TSC2 pathway, a pathway that is frequently mutated in human cancers. Although hypoxia has been shown to inhibit mTOR activity, we show here that the hypoxia-induced inhibition of mTOR activity is attenuated in cells lacking TSC2 or PTEN, resulting in a higher translation rate even under hypoxic conditions. Comparison of mTOR inhibition by hypoxia alone or in combination with rapamycin showed that prolonged exposure to hypoxia was required to fully inhibit mTOR activity even in wild-type cells. Increased mTOR activity and protein synthesis did not translate into enhanced cell proliferation rates. However, lack of TSC2 resulted in a survival advantage when cells were exposed to hypoxia. Protection against hypoxia-induced cell death due to TSC2 deficiency is rapamycin-resistant, suggesting that TSC2 affects an apoptotic pathway. Tumors derived from TSC2 wild-type cells exhibited a growth delay compared with TSC2-deficient tumors, indicating that enhanced mTOR activity is advantageous in the initial phase of tumor growth. Therefore, failure to inhibit mTOR under oxygen-limiting conditions can be affected by upstream activating mutations and increases the survival and growth of hypoxic tumor cells.

Original publication

DOI

10.1158/0008-5472.CAN-05-3375

Type

Journal article

Journal

Cancer Res

Publication Date

01/02/2006

Volume

66

Pages

1561 - 1569

Keywords

Cell Growth Processes, Cell Hypoxia, Cell Line, Tumor, Glioblastoma, Humans, Male, Mutation, Oxygen, PTEN Phosphohydrolase, Phosphatidylinositol 3-Kinases, Prostatic Neoplasms, Protein Biosynthesis, Protein Kinases, RNA, Messenger, Signal Transduction, TOR Serine-Threonine Kinases, Transcription, Genetic, Tuberous Sclerosis Complex 2 Protein, Tumor Suppressor Proteins