High prevalence of mTOR complex activity can be targeted using Torin2 in papillary thyroid carcinoma

被引:40
作者
Ahmed, Maqbool [1 ]
Hussain, Azhar R. [1 ]
Bavi, Prashant [1 ]
Ahmed, Saeeda O. [1 ]
AlSobhi, Saif S. [2 ]
Al-Dayel, Fouad [3 ]
Uddin, Shahab [1 ]
Al-Kuraya, Khawla S. [1 ,4 ,5 ]
机构
[1] King Faisal Specialist Hosp & Res Ctr, Riyadh 11211, Saudi Arabia
[2] King Faisal Specialist Hosp & Res Ctr, Dept Endocrinol, Riyadh 11211, Saudi Arabia
[3] King Faisal Specialist Hosp & Res Ctr, Dept Pathol, Riyadh 11211, Saudi Arabia
[4] Al Faisal Univ, Dept Life Sci, Coll Sci, Riyadh 11533, Saudi Arabia
[5] Al Faisal Univ, Coll Med, Riyadh 11533, Saudi Arabia
关键词
RENAL-CELL CARCINOMA; MAMMALIAN TARGET; INCREASING INCIDENCE; POOR SURVIVAL; CANCER-CELLS; PATHWAY; RAPAMYCIN; THERAPY; KINASE; ACTIVATION;
D O I
10.1093/carcin/bgu051
中图分类号
R73 [肿瘤学];
学科分类号
100214 [肿瘤学];
摘要
The mammalian target of rapamycin (mTOR) signaling cascade is a key regulatory pathway controlling initiation of messenger RNA in mammalian cells. Although dysregulation of mTOR signaling has been reported earlier in cancers, there is paucity of data about mTOR expression in papillary thyroid carcinoma (PTC). Therefore, in this study, we investigated the presence of mTORC2 and mTORC1 complexes in a large cohort of >500 PTC samples. Our clinical data showed the presence of active mTORC1 and mTORC2 in 81 and 39% of PTC samples, respectively. Interestingly, coexpression of mTORC1 and mTORC2 activity was seen in a 32.5% (164/504) of the PTC studied and this association was statistically significant (P = 0.0244). mTOR signaling complex was also found to be associated with activated AKT and 4E-BP1. In vitro, using Torin2, a second-generation mTOR inhibitor or gene silencing of mTOR expression prevented mTORC1 and mTORC2 activity leading to inactivation of P70S6, 4E-BP1, AKT and Bad. Inhibition of mTOR activity led to downregulation of cyclin D1, a gene regulated by messenger RNA translation via phosphorylation of 4E-BP1. Torin2 treatment also inhibited cell viability and induced caspase-dependent apoptosis via activation of mitochondrial apoptotic pathway in PTC cells. Finally, Torin2 treatment induces anticancer effect on PTC xenograft tumor growth in nude mice via inhibition of mTORC1 and mTORC2 and its associated pathways. Our results suggest that coexpression of mTORC1 and mTORC2 is seen frequently in the clinical PTC samples and dual targeting of mTORC1 and mTORC2 activity may be an attractive therapeutic target for treatment of PTC.
引用
收藏
页码:1564 / 1572
页数:9
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