| pubmed-article:18511708 | rdf:type | pubmed:Citation | lld:pubmed |
| pubmed-article:18511708 | lifeskim:mentions | umls-concept:C0027651 | lld:lifeskim |
| pubmed-article:18511708 | lifeskim:mentions | umls-concept:C0345967 | lld:lifeskim |
| pubmed-article:18511708 | lifeskim:mentions | umls-concept:C1844596 | lld:lifeskim |
| pubmed-article:18511708 | lifeskim:mentions | umls-concept:C1708096 | lld:lifeskim |
| pubmed-article:18511708 | lifeskim:mentions | umls-concept:C0038952 | lld:lifeskim |
| pubmed-article:18511708 | lifeskim:mentions | umls-concept:C1710082 | lld:lifeskim |
| pubmed-article:18511708 | lifeskim:mentions | umls-concept:C0086597 | lld:lifeskim |
| pubmed-article:18511708 | pubmed:issue | 5 | lld:pubmed |
| pubmed-article:18511708 | pubmed:dateCreated | 2008-10-17 | lld:pubmed |
| pubmed-article:18511708 | pubmed:abstractText | Solid tumors such as mesothelioma exhibit a stubborn resistance to apoptosis that may derive from survival pathways, such as PI3K/Akt/mTOR, that are activated in many tumors, including mesothelioma. To address the role of PI3K/Akt/mTOR, we used a novel approach to study mesothelioma ex vivo as tumor fragment spheroids. Freshly resected mesothelioma tissue from 15 different patients was grown in vitro as 1- to 2-mm-diameter fragments, exposed to apoptotic agents for 48 hours with or without PI3K/Akt/mTOR inhibitors, and doubly stained for cytokeratin and cleaved caspase 3 to identify apoptotic mesothelioma cells. Mesothelioma cells within the tumor spheroids exhibited striking resistance to apoptotic agents such as TRAIL plus gemcitabine that were highly effective against monolayers. In a majority of tumors (67%; 10 of 15), apoptotic resistance could be reduced by more than 50% by rapamycin, an mTOR inhibitor, but not by LY294002, a PI3K inhibitor. Responsiveness to rapamycin correlated with staining for the mTOR target, p-S6K, in the original tumor, but not for p-Akt. As confirmation of the role of mTOR, siRNA knockdown of S6K reproduced the effect of rapamycin in three rapamycin-responsive tumors. Finally, in 37 mesotheliomas on tissue microarray, p-S6K correlated only weakly with p-Akt, suggesting the existence of Akt-independent regulation of mTOR. We propose that mTOR mediates survival signals in many mesothelioma tumors. Inhibition of mTOR may provide a nontoxic adjunct to therapy directed against malignant mesothelioma, especially in those with high baseline expression of p-S6K. | lld:pubmed |
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| pubmed-article:18511708 | pubmed:language | eng | lld:pubmed |
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| pubmed-article:18511708 | pubmed:citationSubset | IM | lld:pubmed |
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| pubmed-article:18511708 | pubmed:status | MEDLINE | lld:pubmed |
| pubmed-article:18511708 | pubmed:month | Nov | lld:pubmed |
| pubmed-article:18511708 | pubmed:issn | 1535-4989 | lld:pubmed |
| pubmed-article:18511708 | pubmed:author | pubmed-author:SugarbakerDav... | lld:pubmed |
| pubmed-article:18511708 | pubmed:author | pubmed-author:GordonGavin... | lld:pubmed |
| pubmed-article:18511708 | pubmed:author | pubmed-author:BuenoRaphaelR | lld:pubmed |
| pubmed-article:18511708 | pubmed:author | pubmed-author:BroaddusV... | lld:pubmed |
| pubmed-article:18511708 | pubmed:author | pubmed-author:NishimuraStep... | lld:pubmed |
| pubmed-article:18511708 | pubmed:author | pubmed-author:JablonsDavid... | lld:pubmed |
| pubmed-article:18511708 | pubmed:author | pubmed-author:WilsonShannon... | lld:pubmed |
| pubmed-article:18511708 | pubmed:author | pubmed-author:BarboneDarioD | lld:pubmed |
| pubmed-article:18511708 | pubmed:author | pubmed-author:YangTsung-Min... | lld:pubmed |
| pubmed-article:18511708 | pubmed:issnType | Electronic | lld:pubmed |
| pubmed-article:18511708 | pubmed:volume | 39 | lld:pubmed |
| pubmed-article:18511708 | pubmed:owner | NLM | lld:pubmed |
| pubmed-article:18511708 | pubmed:authorsComplete | Y | lld:pubmed |
| pubmed-article:18511708 | pubmed:pagination | 576-83 | lld:pubmed |
| pubmed-article:18511708 | pubmed:dateRevised | 2010-11-18 | lld:pubmed |
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