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mTORC1-mediated downregulation of COX2 restrains tumor growth caused by TSC2 deficiency

Tuberous sclerosis complex (TSC), caused by loss-of-function mutations in the TSC1 or TSC2 gene, is characterized by benign tumor formation in multiple organs. Hyperactivation of mammalian target of rapamycin complex 1 (mTORC1) is the primary alteration underlying TSC tumors. By analyzing Tsc2-null...

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Autores principales: Li, Hongwu, Jin, Fuquan, Jiang, Keguo, Ji, Shuang, Wang, Li, Ni, Zhaofei, Chen, Xianguo, Hu, Zhongdong, Zhang, Hongbing, Liu, Yehai, Qin, Yide, Zha, Xiaojun
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Impact Journals LLC 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5053737/
https://www.ncbi.nlm.nih.gov/pubmed/27078846
http://dx.doi.org/10.18632/oncotarget.8633
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author Li, Hongwu
Jin, Fuquan
Jiang, Keguo
Ji, Shuang
Wang, Li
Ni, Zhaofei
Chen, Xianguo
Hu, Zhongdong
Zhang, Hongbing
Liu, Yehai
Qin, Yide
Zha, Xiaojun
author_facet Li, Hongwu
Jin, Fuquan
Jiang, Keguo
Ji, Shuang
Wang, Li
Ni, Zhaofei
Chen, Xianguo
Hu, Zhongdong
Zhang, Hongbing
Liu, Yehai
Qin, Yide
Zha, Xiaojun
author_sort Li, Hongwu
collection PubMed
description Tuberous sclerosis complex (TSC), caused by loss-of-function mutations in the TSC1 or TSC2 gene, is characterized by benign tumor formation in multiple organs. Hyperactivation of mammalian target of rapamycin complex 1 (mTORC1) is the primary alteration underlying TSC tumors. By analyzing Tsc2-null mouse embryonic fibroblasts (MEFs) and rat uterine leiomyoma-derived Tsc2-null ELT3 cells, we detected evidence for the involvement of cyclooxygenase 2 (COX2) as a downstream target of mTORC1 in the development of TSC tumors. We showed that loss of TSC2 led to decreased COX2 expression through activation of an mTORC1/signal transducer and activator of transcription 3 (STAT3) signaling pathway. Overexpression of COX2 promoted proliferation and tumoral growth of Tsc2-null cells. COX2 knockdown inhibited the proliferation of the control cells. COX2 enhanced Tsc2-null cell growth through upregulation of interleukin-6 (IL-6). In addition, rapamycin in combination with celecoxib, a COX2 inhibitor, strongly inhibited Tsc2-deficient cell growth. We conclude that downregulation of COX2 exerts a protective effect against hyperactivated mTORC1-mediated tumorigenesis caused by the loss of TSC2, and the combination of rapamycin and celecoxib may be an effective new approach to treating TSC.
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spelling pubmed-50537372016-10-12 mTORC1-mediated downregulation of COX2 restrains tumor growth caused by TSC2 deficiency Li, Hongwu Jin, Fuquan Jiang, Keguo Ji, Shuang Wang, Li Ni, Zhaofei Chen, Xianguo Hu, Zhongdong Zhang, Hongbing Liu, Yehai Qin, Yide Zha, Xiaojun Oncotarget Research Paper Tuberous sclerosis complex (TSC), caused by loss-of-function mutations in the TSC1 or TSC2 gene, is characterized by benign tumor formation in multiple organs. Hyperactivation of mammalian target of rapamycin complex 1 (mTORC1) is the primary alteration underlying TSC tumors. By analyzing Tsc2-null mouse embryonic fibroblasts (MEFs) and rat uterine leiomyoma-derived Tsc2-null ELT3 cells, we detected evidence for the involvement of cyclooxygenase 2 (COX2) as a downstream target of mTORC1 in the development of TSC tumors. We showed that loss of TSC2 led to decreased COX2 expression through activation of an mTORC1/signal transducer and activator of transcription 3 (STAT3) signaling pathway. Overexpression of COX2 promoted proliferation and tumoral growth of Tsc2-null cells. COX2 knockdown inhibited the proliferation of the control cells. COX2 enhanced Tsc2-null cell growth through upregulation of interleukin-6 (IL-6). In addition, rapamycin in combination with celecoxib, a COX2 inhibitor, strongly inhibited Tsc2-deficient cell growth. We conclude that downregulation of COX2 exerts a protective effect against hyperactivated mTORC1-mediated tumorigenesis caused by the loss of TSC2, and the combination of rapamycin and celecoxib may be an effective new approach to treating TSC. Impact Journals LLC 2016-04-07 /pmc/articles/PMC5053737/ /pubmed/27078846 http://dx.doi.org/10.18632/oncotarget.8633 Text en Copyright: © 2016 Li et al. http://creativecommons.org/licenses/by/2.5/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Paper
Li, Hongwu
Jin, Fuquan
Jiang, Keguo
Ji, Shuang
Wang, Li
Ni, Zhaofei
Chen, Xianguo
Hu, Zhongdong
Zhang, Hongbing
Liu, Yehai
Qin, Yide
Zha, Xiaojun
mTORC1-mediated downregulation of COX2 restrains tumor growth caused by TSC2 deficiency
title mTORC1-mediated downregulation of COX2 restrains tumor growth caused by TSC2 deficiency
title_full mTORC1-mediated downregulation of COX2 restrains tumor growth caused by TSC2 deficiency
title_fullStr mTORC1-mediated downregulation of COX2 restrains tumor growth caused by TSC2 deficiency
title_full_unstemmed mTORC1-mediated downregulation of COX2 restrains tumor growth caused by TSC2 deficiency
title_short mTORC1-mediated downregulation of COX2 restrains tumor growth caused by TSC2 deficiency
title_sort mtorc1-mediated downregulation of cox2 restrains tumor growth caused by tsc2 deficiency
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5053737/
https://www.ncbi.nlm.nih.gov/pubmed/27078846
http://dx.doi.org/10.18632/oncotarget.8633
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