Oncogenic effects of urotensin-II in cells lacking tuberous sclerosis complex-2

Goldberg, Alexander A.; Joung, Kwang-Bo; Mansuri, Asma; Kang, Yujin; Echavarría, Raquel; Nikolajev, Ljiljana; Sun, Yangying; Yu, Jane; Laporte, Stéphane A.; Schwertani, Adel; Kristof, Arnold S.

doi:10.18632/oncotarget.10748

Cited by 5 publications

(4 citation statements)

References 52 publications

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“…5D). Recently, a disease-associated recurrent Rheb Tyr35Asn (Y35N) mutation has been identified in kidney and endometrial carcinomas, and this mutant form of Rheb activates mTORC1 and promotes tumorigenesis (33). We overexpressed a wild-type Rheb and Rheb Y35N in HEK293T cells, and then assessed the protein levels of EP3.…”

Section: Rheb Is a Critical Mediator Of Ep3 Expression In Cells With mentioning

confidence: 99%

Tuberin Regulates Prostaglandin Receptor–Mediated Viability, via Rheb, in mTORC1-Hyperactive Cells

Liu

Zhang

et al. 2017

Molecular Cancer Research

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Tuberous sclerosis complex (TSC) is a tumor-suppressor syndrome affecting multiple organs, including the brain, skin, kidneys, heart, and lungs. TSC is associated with mutations in or resulting in hyperactivation of mTOR complex 1 (mTORC1). Clinical trials demonstrate that mTORC1 inhibitors decrease tumor volume and stabilize lung function in TSC patients; however, mTOR inhibitors are cytostatic not cytocidal, and long-term benefits and toxicities are uncertain. Previously, we identified rapamycin-insensitive upregulation of cyclooxygenase 2 (PTGS2/COX2) and prostaglandin E2 (PGE2) production in TSC2-deficient cells and postulated that the action of excess PGE2 and its cognate receptors (EP) contributes to cell survival. In this study, we identify upregulation of EP3 (PTGER3) expression in TSC2-deficient cells, TSC renal angiomyolipomas, lymphangioleiomyomatosis lung nodules, and epileptic brain tubers. TSC2 negatively regulated EP3 expression via Rheb in a rapamycin-insensitive manner. The EP3 antagonist, L-798106, selectively suppressed the viability of TSC2-deficient cells and decreased the lung colonization of TSC2-deficient cells. Collectively, these data reveal a novel function of TSC2 and Rheb in the regulation of EP3 expression and cell viability. Therapeutic targeting of an aberrant PGE2-EP3 signaling axis may have therapeutic benefit for TSC patients and for other mTOR-hyperactive neoplasms. .

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Section: Rheb Is a Critical Mediator Of Ep3 Expression In Cells With mentioning

confidence: 99%

Tuberin Regulates Prostaglandin Receptor–Mediated Viability, via Rheb, in mTORC1-Hyperactive Cells

Liu

Zhang

et al. 2017

Molecular Cancer Research

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“…Tuberous sclerosis complex (TSC) is an autosomal dominant disorder characterized by the formation of benign tumors in multiple organs including kidney, brain, skin, and heart, which is caused by inactivating mutations in either of two tumor suppressor genes: TSC1 or TSC2 [ 9 – 11 ]. TSC1 and TSC2 form a functional complex that is a suppressor upstream of mTORC1 [ 12 , 13 ].…”

Section: Introductionmentioning

confidence: 99%

Hyperactivated mTORC1 downregulation of FOXO3a/PDGFRα/AKT cascade restrains tuberous sclerosis complex-associated tumor development

Wang

Liu

et al. 2017

Oncotarget

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Hyperactivation of mammalian target of rapamycin complex 1 (mTORC1), caused by loss-of-function mutations in either the TSC1 or TSC2 gene, leads to the development of tuberous sclerosis complex (TSC), a benign tumor syndrome with multiple affected organs. mTORC1-mediated inhibition of AKT constrains the tumor progression of TSC, but the exact mechanisms remain unclear. Herein we showed that loss of TSC1 or TSC2 downregulation of platelet-derived growth factor receptor α (PDGFRα) expression was mediated by mTORC1. Moreover, mTORC1 inhibited PDGFRα expression via suppression of forkhead box O3a (FOXO3a)-mediated PDGFRα gene transcription. In addition, ectopic expression of PDGFRα promoted AKT activation and enhanced proliferation and tumorigenic capacity of Tsc1- or Tsc2-null mouse embryonic fibroblasts (MEFs), and vice versa. Most importantly, rapamycin in combination with AG1295, a PDGFR inhibitor, significantly inhibited growth of TSC1/TSC2 complex-deficient cells in vitro and in vivo. Therefore, downregulated FOXO3a/PDGFRα/AKT pathway exerts a protective effect against hyperactivated mTORC1-induced tumorigenesis caused by loss of TSC1/TSC2 complex, and the combination of rapamycin and AG1295 may be a new effective strategy for TSC-associated tumors treatment.

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“…In another study in hepatocellular carcinoma, urotensin-II/UTR induced ROS generation through NADPH oxidase, activated MAPK8/9 pathways, and increased expression of MMP2, CYBA, NCF4, NCF1, NCF2, CYBB, PCNA, FSCN1, which are involved in migration and invasion (Li et al 2017). Urotensin-II induced proliferation and migration via MAPK and FAK pathways in TSC2-deficient human angiomyolipoma cells excised from a patient with Lymphangioleiomyomatosis (LAM) (Goldberg et al 2016). In lung adenocarcinoma tumor-bearing nude mice model, urotensin-II forms an inflammatory microenvironment by increased expression of IL-6, TNF-α and MMP-9 via NF-kB pathway leading to enhanced proliferation (Zhou et al 2012).…”

Section: Cancermentioning

confidence: 99%

The network map of urotensin-II mediated signaling pathway in physiological and pathological conditions

Rex

Suchitha

Palollathil

et al. 2022

J. Cell Commun. Signal.

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Urotensin‐II is a polypeptide ligand with neurohormone‐like activity. It mediates downstream signaling pathways through G‐protein‐coupled receptor 14 (GPR14) also known as urotensin receptor (UTR). Urotensin‐II is the most potent endogenous vasoconstrictor in mammals, promoting cardiovascular remodelling, cardiac fibrosis, and cardiomyocyte hypertrophy. It is also involved in other physiological and pathological activities, including neurosecretory effects, insulin resistance, atherosclerosis, kidney disease, and carcinogenic effects. Moreover, it is a notable player in the process of inflammatory injury, which leads to the development of inflammatory diseases. Urotensin‐II/UTR expression stimulates the accumulation of monocytes and macrophages, which promote the adhesion molecules expression, chemokines activation and release of inflammatory cytokines at inflammatory injury sites. Therefore, urotensin‐II turns out to be an important therapeutic target for the treatment options and management of associated diseases. The main downstream signaling pathways mediated through this urotensin‐II /UTR system are RhoA/ROCK, MAPKs and PI3K/AKT. Due to the importance of urotensin‐II systems in biomedicine, we consolidated a network map of urotensin‐II /UTR signaling. The described signaling map comprises 33 activation/inhibition events, 31 catalysis events, 15 molecular associations, 40 gene regulation events, 60 types of protein expression, and 11 protein translocation events. The urotensin‐II signaling pathway map is made freely accessible through the WikiPathways Database (https://www.wikipathways.org/index.php/Pathway:WP5158). The availability of comprehensive urotensin‐II signaling in the public resource will help understand the regulation and function of this pathway in normal and pathological conditions. We believe this resource will provide a platform to the scientific community in facilitating the identification of novel therapeutic drug targets for diseases associated with urotensin‐II signaling.

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Oncogenic effects of urotensin-II in cells lacking tuberous sclerosis complex-2

Cited by 5 publications

References 52 publications

Tuberin Regulates Prostaglandin Receptor–Mediated Viability, via Rheb, in mTORC1-Hyperactive Cells

Tuberin Regulates Prostaglandin Receptor–Mediated Viability, via Rheb, in mTORC1-Hyperactive Cells

Hyperactivated mTORC1 downregulation of FOXO3a/PDGFRα/AKT cascade restrains tuberous sclerosis complex-associated tumor development

The network map of urotensin-II mediated signaling pathway in physiological and pathological conditions

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