title: mTORC1 enhancement of STIM1-mediated store-operated Ca2+ entry constrains tuberous sclerosis complex-related tumor development.
abstract: The protein complex of tuberous sclerosis complex (TSC)1 and TSC2 tumor suppressors is a key negative regulator of mammalian target of rapamycin (mTOR). Hyperactive mTOR signaling due to the loss-of-function of mutations in either TSC1 or TSC2 gene causes TSC, an autosomal dominant disorder featured with benign tumors in multiple organs. As the ubiquitous second messenger calcium (Ca(2+)) regulates various cellular processes involved in tumorigenesis, we explored the potential role of mTOR in modulation of cellular Ca(2+) homeostasis, and in turn the effect of Ca(2+) signaling in TSC-related tumor development. We found that loss of Tsc2 potentiated store-operated Ca(2+) entry (SOCE) in an mTOR complex 1 (mTORC1)-dependent way. The endoplasmic reticulum Ca(2+) sensor, stromal interaction molecule 1 (STIM1), was upregulated in Tsc2-deficient cells, and was suppressed by mTORC1 inhibitor rapamycin. In addition, SOCE repressed AKT1 phosphorylation. Blocking SOCE either by depleting STIM1 or ectopically expressing dominant-negative Orai1 accelerated TSC-related tumor development, likely because of restored AKT1 activity and enhanced tumor angiogenesis. Our data, therefore, suggest that mTORC1 enhancement of store-operated Ca(2+) signaling hinders TSC-related tumor growth through suppression of AKT1 signaling. The augmented SOCE by hyperactive mTORC1-STIM1 cascade may contribute to the benign nature of TSC-related tumors. Application of SOCE agonists could thus be a contraindication for TSC patients. In contrast, SOCE agonists should attenuate mTOR inhibitors-mediated AKT reactivation and consequently potentiate their efficacy in the treatment of the patients with TSC.
authors.affiliation: Department of Physiology and Pathophysiology, State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences and School of Basic Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
authors.forename: H
authors.initials: H
authors.lastname: Peng
authors.forename: J
authors.initials: J
authors.lastname: Liu
authors.forename: Q
authors.initials: Q
authors.lastname: Sun
authors.forename: R
authors.initials: R
authors.lastname: Chen
authors.forename: Y
authors.initials: Y
authors.lastname: Wang
authors.forename: J
authors.initials: J
authors.lastname: Duan
authors.forename: C
authors.initials: C
authors.lastname: Li
authors.forename: B
authors.initials: B
authors.lastname: Li
authors.forename: Y
authors.initials: Y
authors.lastname: Jing
authors.forename: X
authors.initials: X
authors.lastname: Chen
authors.forename: Q
authors.initials: Q
authors.lastname: Mao
authors.forename: K-F
authors.initials: KF
authors.lastname: Xu
authors.forename: C L
authors.initials: CL
authors.lastname: Walker
authors.forename: J
authors.initials: J
authors.lastname: Li
authors.forename: J
authors.initials: J
authors.lastname: Wang
authors.forename: H
authors.initials: H
authors.lastname: Zhang
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D015220:Calcium Channels / Q000235:genetics / Q000502:physiology; D020013:Calcium Signaling / Q000502:physiology*; D002460:Cell Line; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic; D005260:Female; D005347:Fibroblasts; D006801:Humans; D007680:Kidney Neoplasms / Q000235:genetics / Q000473:pathology; D007889:Leiomyoma / Q000473:pathology; D000076222:Mechanistic Target of Rapamycin Complex 1; D008565:Membrane Proteins / Q000502:physiology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D046912:Multiprotein Complexes / Q000502:physiology*; D009363:Neoplasm Proteins / Q000502:physiology*; D009389:Neovascularization, Pathologic / Q000503:physiopathology; D000071740:ORAI1 Protein; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D034622:RNA Interference; D051381:Rats; D011993:Recombinant Fusion Proteins / Q000502:physiology; D000071737:Stromal Interaction Molecule 1; D058570:TOR Serine-Threonine Kinases / Q000502:physiology*; D014402:Tuberous Sclerosis / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D000077005:Tuberous Sclerosis Complex 2 Protein; D047988:Tumor Necrosis Factor Receptor-Associated Peptides and Proteins / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000502:physiology; D014594:Uterine Neoplasms / Q000473:pathology
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D015220:Calcium Channels; D008565:Membrane Proteins; D046912:Multiprotein Complexes; D009363:Neoplasm Proteins; D000071740:ORAI1 Protein; C510746:ORAI1 protein, human; D011993:Recombinant Fusion Proteins; C103530:STIM1 protein, human; D000071737:Stromal Interaction Molecule 1; C414202:TRAF3IP2 protein, human; C000624653:TSC2 protein, human; C000624654:Tsc2 protein, mouse; C000624655:Tsc2 protein, rat; D000077005:Tuberous Sclerosis Complex 2 Protein; D047988:Tumor Necrosis Factor Receptor-Associated Peptides and Proteins; D025521:Tumor Suppressor Proteins; C546842:MTOR protein, human; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases