title: mTORC1-mediated downregulation of COX2 restrains tumor growth caused by TSC2 deficiency.
abstract: 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.
authors.affiliation: Department of Otorhinolaryngology, Head & Neck Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei, China.|Department of Otorhinolaryngology, Head & Neck Surgery, The Fourth Affiliated Hospital of Anhui Medical University, Hefei, China.
authors.forename: Hongwu
authors.initials: H
authors.lastname: Li
authors.affiliation: Department of Biochemistry & Molecular Biology, School of Basic Medicine, Anhui Medical University, Hefei, China.|School of Pharmacy, Anhui Medical University, Hefei, China.
authors.forename: Fuquan
authors.initials: F
authors.lastname: Jin
authors.affiliation: Department of Biochemistry & Molecular Biology, School of Basic Medicine, Anhui Medical University, Hefei, China.|Department of Nephrology, The Third Affiliated Hospital of Anhui Medical University, Hefei, China.
authors.forename: Keguo
authors.initials: K
authors.lastname: Jiang
authors.affiliation: Department of Biochemistry & Molecular Biology, School of Basic Medicine, Anhui Medical University, Hefei, China.
authors.forename: Shuang
authors.initials: S
authors.lastname: Ji
authors.affiliation: Department of Biochemistry & Molecular Biology, School of Basic Medicine, Anhui Medical University, Hefei, China.
authors.forename: Li
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Biochemistry & Molecular Biology, School of Basic Medicine, Anhui Medical University, Hefei, China.
authors.forename: Zhaofei
authors.initials: Z
authors.lastname: Ni
authors.affiliation: Department of Urology, The First Affiliated Hospital of Anhui Medical University, Hefei, China.
authors.forename: Xianguo
authors.initials: X
authors.lastname: Chen
authors.affiliation: Modern Research Center for Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China.
authors.forename: Zhongdong
authors.initials: Z
authors.lastname: Hu
authors.affiliation: State Key Laboratory of Medical Molecular Biology, Department of Physiology & Pathophysiology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.
authors.forename: Hongbing
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Department of Otorhinolaryngology, Head & Neck Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei, China.
authors.forename: Yehai
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Biochemistry & Molecular Biology, School of Basic Medicine, Anhui Medical University, Hefei, China.
authors.forename: Yide
authors.initials: Y
authors.lastname: Qin
authors.affiliation: Department of Biochemistry & Molecular Biology, School of Basic Medicine, Anhui Medical University, Hefei, China.|State Key Laboratory Incubation Base of Dermatology, Ministry of National Science and Technology, Hefei, China.
authors.forename: Xiaojun
authors.initials: X
authors.lastname: Zha
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D063646:Carcinogenesis / Q000378:metabolism; D000068579:Celecoxib / Q000494:pharmacology; D049109:Cell Proliferation / Q000187:drug effects; D051546:Cyclooxygenase 2 / Q000096:biosynthesis*; D015536:Down-Regulation; D000076222:Mechanistic Target of Rapamycin Complex 1 / Q000378:metabolism*; D051379:Mice; D009369:Neoplasms / Q000235:genetics* / Q000378:metabolism; D051381:Rats; D020123:Sirolimus / Q000494:pharmacology; D014402:Tuberous Sclerosis / Q000150:complications* / Q000378:metabolism / Q000473:pathology; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins / Q000172:deficiency*
chemical_list: C000624654:Tsc2 protein, mouse; C000624655:Tsc2 protein, rat; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins; D051546:Cyclooxygenase 2; D000076222:Mechanistic Target of Rapamycin Complex 1; D000068579:Celecoxib; D020123:Sirolimus
keywords: COX2; IL-6; STAT3; TSC; mTOR