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Therapeutic Targeting of the Secreted Lysophospholipase D Autotaxin Suppresses Tuberous Sclerosis Complex-Associated Tumorigenesis
- Source :
- Cancer Res
- Publication Year :
- 2019
-
Abstract
- Tuberous sclerosis complex (TSC) is an autosomal dominant disease characterized by multiorgan hamartomas, including renal angiomyolipomas and pulmonary lymphangioleiomyomatosis (LAM). TSC2 deficiency leads to hyperactivation of mTOR Complex 1 (mTORC1), a master regulator of cell growth and metabolism. Phospholipid metabolism is dysregulated upon TSC2 loss, causing enhanced production of lysophosphatidylcholine (LPC) species by TSC2-deficient tumor cells. LPC is the major substrate of the secreted lysophospholipase D autotaxin (ATX), which generates two bioactive lipids, lysophosphatidic acid (LPA) and sphingosine-1-phosphate (S1P). We report here that ATX expression is upregulated in human renal angiomyolipoma-derived TSC2-deficient cells compared with TSC2 add-back cells. Inhibition of ATX via the clinically developed compound GLPG1690 suppressed TSC2-loss associated oncogenicity in vitro and in vivo and induced apoptosis in TSC2-deficient cells. GLPG1690 suppressed AKT and ERK1/2 signaling and profoundly impacted the transcriptome of these cells while inducing minor gene expression changes in TSC2 add-back cells. RNA-sequencing studies revealed transcriptomic signatures of LPA and S1P, suggesting an LPA/S1P-mediated reprogramming of the TSC lipidome. In addition, supplementation of LPA or S1P rescued proliferation and viability, neutral lipid content, and AKT or ERK1/2 signaling in human TSC2-deficient cells treated with GLPG1690. Importantly, TSC-associated renal angiomyolipomas have higher expression of LPA receptor 1 and S1P receptor 3 compared with normal kidney. These studies increase our understanding of TSC2-deficient cell metabolism, leading to novel potential therapeutic opportunities for TSC and LAM. Significance: This study identifies activation of the ATX–LPA/S1P pathway as a novel mode of metabolic dysregulation upon TSC2 loss, highlighting critical roles for ATX in TSC2-deficient cell fitness and in TSC tumorigenesis.
- Subjects :
- 0301 basic medicine
Cancer Research
congenital, hereditary, and neonatal diseases and abnormalities
Angiomyolipoma
Apoptosis
mTORC1
Article
03 medical and health sciences
chemistry.chemical_compound
Mice
0302 clinical medicine
Cell Movement
Mice, Inbred NOD
Sphingosine
Tuberous Sclerosis
Lysophosphatidic acid
Tuberous Sclerosis Complex 2 Protein
Tumor Cells, Cultured
Animals
Humans
Protein kinase B
Ataxin-1
Cell Proliferation
Mice, Knockout
Cell growth
Chemistry
Imidazoles
Autosomal dominant trait
Kidney Neoplasms
nervous system diseases
030104 developmental biology
Cell Transformation, Neoplastic
Pyrimidines
Oncology
030220 oncology & carcinogenesis
Cancer research
lipids (amino acids, peptides, and proteins)
Female
Signal transduction
Autotaxin
TSC2
Lysophospholipids
Signal Transduction
Subjects
Details
- ISSN :
- 15387445
- Volume :
- 80
- Issue :
- 13
- Database :
- OpenAIRE
- Journal :
- Cancer research
- Accession number :
- edsair.doi.dedup.....d42ce41c0a1aaf146c4cb543b50e770c