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Silic-Benussi 2016a Abstract Mito Xmas Meeting Innsbruck

From Bioblast
mTORC inhibition increases ROS levels and induces cell death in T-ALL cells.

Link:

Silic-Benussi M, Linseisen M, Urso L, Cavallari I, Minuzzo S, del Bianco P, Rende F, Scattolin G, Basso G, Indraccolo S, D’Agostino DM, Ciminale V (2016)

Event: Mito Xmas Meeting 2016 Innsbruck AT

Approximately 20% of T-cell acute lymphoblastic leukemia (T-ALL) patients do not respond to current therapy, and their clinical outcome is dismal. The PI3K/Akt/mTOR oncogenic pathway is commonly found hyper-activated in T-ALL. In addition to controlling cell growth and autophagy, mTORC1 influences mitochondrial activity and oxidative metabolism by controlling the interaction between YY1 and PGC1.

In previous studies, we showed that T-ALL cells exhibit high levels of mitochondrial reactive oxygen species (ROS). ROS are powerful signalling molecules that can induce apoptosis through p53 activation, but may also increase cancer cell survival through PTEN oxidation, which results in an increased Akt activity.

In the present study, we aimed at testing the possible cross-talk between mTOR and ROS in T-ALL. Interestingly, in vitro studies revealed that the mTORC1-inhibitor Everolimus increased ROS levels and induced cell death both in T-ALL cell lines and patient-derived T-ALL xenografts (PDTALL) but not in primary normal thymocytes. In addition, Everolimus increased the dexamethasone sensitivity of the glucocorticoid-resistant PDTALL19 in vitro. The finding that Everolimus-induced cell death was reduced by pre-treatment with the ROS scavenger N-acetyl-cystein (NAC) indicates that this effect was ROS-dependen. In vivo experiments carried out using PDTALL cells showed that Everolimus significantly reduced the number of leukemic cells and increased the survival of treated-mice.

These studies indicate a connection between mTOR and ROS, and suggest that mTORC1 inhibition may prove to be effective to overcome dexamethasone-resistance of refractory T-ALL patients.


Labels: Pathology: Other 





Event: B2, Oral 


Affiliations

Silic-Benussi M(1,2), Linseisen M(1), Urso L(1), Cavallari I(1), Minuzzo S(1), del Bianco P(2), Rende F(1), Scattolin G(1), Basso G(3), Indraccolo S(2), D’Agostino DM(4), Ciminale V(1,2)
  1. Dept Surgery, Oncology, Gastroenterology, Univ Padova, Italy
  2. Istituto Oncologico Veneto-IRRCS, Padova, Italy
  3. Dept Woman Child Health, Haemato-Oncology Division, Univ Padova, Italy
  4. Dept Biomedical Sc, Univ Padova, Italy