Mammalian target of rapamycin contributes to the acquired apoptotic resistance of human mesothelioma multicellular spheroids

Dario Barbone, Tsung Ming Yang, Jeffrey R. Morgan, Giovanni Gaudino, V. Courtney Broaddus

Risultato della ricerca: Contributo su rivistaArticolo in rivistapeer review

Abstract

When grown as three-dimensional structures, tumor cells can acquire an additional multicellular resistance to apoptosis that may mimic the chemoresistance found in solid tumors. We developed a multicellular spheroid model of malignant mesothelioma to investigate molecular mechanisms of acquired apoptotic resistance. We found that mesothelioma cell lines, when grown as multicellular spheroids, acquired resistance to a variety of apoptotic stimuli, including combinations of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), ribotoxic stressors, histone deacetylase, and proteasome inhibitors, that were highly effective against mesothelioma cells when grown as monolayers. Inhibitors of the phosphatidylinositol 3-kinase/Akt/mammalian target of rapamycin (mTOR) pathway, particularly rapamycin, blocked much of the acquired resistance of the spheroids, suggesting a key role for mTOR. Knockdown by small interference RNA of S6K, a major downstream target of mTOR, reproduced the effect of rapamycin, thereby confirming the role of mTOR and of S6K in the acquired resistance of three-dimensional spheroids. Rapamycin or S6K knockdown increased TRAIL-induced caspase-8 cleavage in spheroids, suggesting initially that mTOR inhibited apoptosis by actions at the death receptor pathway; however, isolation of the apoptotic pathways by means of Bid knockdown ablated this effect showing that mTOR actually controls a step distal to Bid, probably at the level of the mitochondria. In sum, mTOR and S6K contribute to the apoptotic resistance of mesothelioma cells in three-dimensional, not in two-dimensional, cultures. The three-dimensional model may reflect a more clinically relevant in vitro setting in which mTOR exhibits anti-apoptotic properties.

Lingua originaleInglese
pagine (da-a)13021-13030
Numero di pagine10
RivistaJournal of Biological Chemistry
Volume283
Numero di pubblicazione19
DOI
Stato di pubblicazionePubblicato - 9 mag 2008
Pubblicato esternamente

Fingerprint

Entra nei temi di ricerca di 'Mammalian target of rapamycin contributes to the acquired apoptotic resistance of human mesothelioma multicellular spheroids'. Insieme formano una fingerprint unica.

Cita questo