title: High prevalence of mTOR complex activity can be targeted using Torin2 in papillary thyroid carcinoma.
abstract: 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.
authors.affiliation: Human Cancer Genomic Research.
authors.forename: Maqbool
authors.initials: M
authors.lastname: Ahmed
authors.affiliation: Human Cancer Genomic Research.
authors.forename: Azhar R
authors.initials: AR
authors.lastname: Hussain
authors.affiliation: Human Cancer Genomic Research.
authors.forename: Prashant
authors.initials: P
authors.lastname: Bavi
authors.affiliation: Human Cancer Genomic Research.
authors.forename: Saeeda O
authors.initials: SO
authors.lastname: Ahmed
authors.affiliation: Department of Endocrinology and.
authors.forename: Saif S
authors.initials: SS
authors.lastname: Al Sobhi
authors.affiliation: Department of Pathology, King Faisal Specialist Hospital and Research Center, Riyadh 11211, Saudi Arabia and.
authors.forename: Fouad
authors.initials: F
authors.lastname: Al-Dayel
authors.affiliation: Human Cancer Genomic Research.
authors.forename: Shahab
authors.initials: S
authors.lastname: Uddin
authors.affiliation: Human Cancer Genomic Research, Department of Life Science, College of Science and College of Medicine, Al-Faisal University, Riyadh 11533, Saudi Arabia kkuraya@kfshrc.edu.sa.
authors.forename: Khawla S
authors.initials: KS
authors.lastname: Al-Kuraya
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D018263:Adenocarcinoma, Follicular / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D002291:Carcinoma, Papillary / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D020169:Caspases / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D018797:Cell Cycle Proteins; D049109:Cell Proliferation / Q000187:drug effects; D015331:Cohort Studies; D005260:Female; D006801:Humans; D007124:Immunoenzyme Techniques; D008297:Male; D000076222:Mechanistic Target of Rapamycin Complex 1; D000076225:Mechanistic Target of Rapamycin Complex 2; D051379:Mice; D008819:Mice, Nude; D008875:Middle Aged; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D046912:Multiprotein Complexes / Q000378:metabolism; D009287:Naphthyridines / Q000494:pharmacology*; D009367:Neoplasm Staging; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation; D011379:Prognosis; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D013964:Thyroid Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D046888:Tissue Array Analysis; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D020169:Caspases; D018797:Cell Cycle Proteins; D000076222:Mechanistic Target of Rapamycin Complex 1; D000076225:Mechanistic Target of Rapamycin Complex 2; D046912:Multiprotein Complexes; D009287:Naphthyridines; D019869:Phosphatidylinositol 3-Kinases; D010750:Phosphoproteins; D051057:Proto-Oncogene Proteins c-akt; D034741:RNA, Small Interfering; D058570:TOR Serine-Threonine Kinases; C558529:9-(6-aminopyridin-3-yl)-1-(3-(trifluoromethyl)phenyl)benzo(h)(1,6)naphthyridin-2(1H)-one; C087000:EIF4EBP1 protein, human; C546842:MTOR protein, human