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Upregulation of acid ceramidase contributes to tumor progression in tuberous sclerosis complex

Tuberous sclerosis complex (TSC) is characterized by multisystem, low-grade neoplasia involving the lung, kidneys, brain, and heart. Lymphangioleiomyomatosis (LAM) is a progressive pulmonary disease affecting almost exclusively women. TSC and LAM are both caused by mutations in TSC1 and TSC2 that re...

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Autores principales: Astrinidis, Aristotelis, Li, Chenggang, Zhang, Erik Y., Zhao, Xueheng, Zhao, Shuyang, Guo, Minzhe, Olatoke, Tasnim, Mattam, Ushodaya, Huang, Rong, Zhang, Alan G., Pitstick, Lori, Kopras, Elizabeth J., Gupta, Nishant, Jandarov, Roman, Smith, Eric P., Fugate, Elizabeth, Lindquist, Diana, Markiewski, Maciej M., Karbowniczek, Magdalena, Wikenheiser-Brokamp, Kathryn A., Setchell, Kenneth D. R., McCormack, Francis X., Xu, Yan, Yu, Jane J.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Society for Clinical Investigation 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10243802/
https://www.ncbi.nlm.nih.gov/pubmed/36927688
http://dx.doi.org/10.1172/jci.insight.166850
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author Astrinidis, Aristotelis
Li, Chenggang
Zhang, Erik Y.
Zhao, Xueheng
Zhao, Shuyang
Guo, Minzhe
Olatoke, Tasnim
Mattam, Ushodaya
Huang, Rong
Zhang, Alan G.
Pitstick, Lori
Kopras, Elizabeth J.
Gupta, Nishant
Jandarov, Roman
Smith, Eric P.
Fugate, Elizabeth
Lindquist, Diana
Markiewski, Maciej M.
Karbowniczek, Magdalena
Wikenheiser-Brokamp, Kathryn A.
Setchell, Kenneth D. R.
McCormack, Francis X.
Xu, Yan
Yu, Jane J.
author_facet Astrinidis, Aristotelis
Li, Chenggang
Zhang, Erik Y.
Zhao, Xueheng
Zhao, Shuyang
Guo, Minzhe
Olatoke, Tasnim
Mattam, Ushodaya
Huang, Rong
Zhang, Alan G.
Pitstick, Lori
Kopras, Elizabeth J.
Gupta, Nishant
Jandarov, Roman
Smith, Eric P.
Fugate, Elizabeth
Lindquist, Diana
Markiewski, Maciej M.
Karbowniczek, Magdalena
Wikenheiser-Brokamp, Kathryn A.
Setchell, Kenneth D. R.
McCormack, Francis X.
Xu, Yan
Yu, Jane J.
author_sort Astrinidis, Aristotelis
collection PubMed
description Tuberous sclerosis complex (TSC) is characterized by multisystem, low-grade neoplasia involving the lung, kidneys, brain, and heart. Lymphangioleiomyomatosis (LAM) is a progressive pulmonary disease affecting almost exclusively women. TSC and LAM are both caused by mutations in TSC1 and TSC2 that result in mTORC1 hyperactivation. Here, we report that single-cell RNA sequencing of LAM lungs identified activation of genes in the sphingolipid biosynthesis pathway. Accordingly, the expression of acid ceramidase (ASAH1) and dihydroceramide desaturase (DEGS1), key enzymes controlling sphingolipid and ceramide metabolism, was significantly increased in TSC2-null cells. TSC2 negatively regulated the biosynthesis of tumorigenic sphingolipids, and suppression of ASAH1 by shRNA or the inhibitor ARN14976 (17a) resulted in markedly decreased TSC2-null cell viability. In vivo, 17a significantly decreased the growth of TSC2-null cell–derived mouse xenografts and short-term lung colonization by TSC2-null cells. Combined rapamycin and 17a treatment synergistically inhibited renal cystadenoma growth in Tsc2(+/–) mice, consistent with increased ASAH1 expression and activity being rapamycin insensitive. Collectively, the present study identifies rapamycin-insensitive ASAH1 upregulation in TSC2-null cells and tumors and provides evidence that targeting aberrant sphingolipid biosynthesis pathways has potential therapeutic value in mechanistic target of rapamycin complex 1–hyperactive neoplasms, including TSC and LAM.
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spelling pubmed-102438022023-06-07 Upregulation of acid ceramidase contributes to tumor progression in tuberous sclerosis complex Astrinidis, Aristotelis Li, Chenggang Zhang, Erik Y. Zhao, Xueheng Zhao, Shuyang Guo, Minzhe Olatoke, Tasnim Mattam, Ushodaya Huang, Rong Zhang, Alan G. Pitstick, Lori Kopras, Elizabeth J. Gupta, Nishant Jandarov, Roman Smith, Eric P. Fugate, Elizabeth Lindquist, Diana Markiewski, Maciej M. Karbowniczek, Magdalena Wikenheiser-Brokamp, Kathryn A. Setchell, Kenneth D. R. McCormack, Francis X. Xu, Yan Yu, Jane J. JCI Insight Research Article Tuberous sclerosis complex (TSC) is characterized by multisystem, low-grade neoplasia involving the lung, kidneys, brain, and heart. Lymphangioleiomyomatosis (LAM) is a progressive pulmonary disease affecting almost exclusively women. TSC and LAM are both caused by mutations in TSC1 and TSC2 that result in mTORC1 hyperactivation. Here, we report that single-cell RNA sequencing of LAM lungs identified activation of genes in the sphingolipid biosynthesis pathway. Accordingly, the expression of acid ceramidase (ASAH1) and dihydroceramide desaturase (DEGS1), key enzymes controlling sphingolipid and ceramide metabolism, was significantly increased in TSC2-null cells. TSC2 negatively regulated the biosynthesis of tumorigenic sphingolipids, and suppression of ASAH1 by shRNA or the inhibitor ARN14976 (17a) resulted in markedly decreased TSC2-null cell viability. In vivo, 17a significantly decreased the growth of TSC2-null cell–derived mouse xenografts and short-term lung colonization by TSC2-null cells. Combined rapamycin and 17a treatment synergistically inhibited renal cystadenoma growth in Tsc2(+/–) mice, consistent with increased ASAH1 expression and activity being rapamycin insensitive. Collectively, the present study identifies rapamycin-insensitive ASAH1 upregulation in TSC2-null cells and tumors and provides evidence that targeting aberrant sphingolipid biosynthesis pathways has potential therapeutic value in mechanistic target of rapamycin complex 1–hyperactive neoplasms, including TSC and LAM. American Society for Clinical Investigation 2023-05-08 /pmc/articles/PMC10243802/ /pubmed/36927688 http://dx.doi.org/10.1172/jci.insight.166850 Text en © 2023 Astrinidis et al. https://creativecommons.org/licenses/by/4.0/This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Research Article
Astrinidis, Aristotelis
Li, Chenggang
Zhang, Erik Y.
Zhao, Xueheng
Zhao, Shuyang
Guo, Minzhe
Olatoke, Tasnim
Mattam, Ushodaya
Huang, Rong
Zhang, Alan G.
Pitstick, Lori
Kopras, Elizabeth J.
Gupta, Nishant
Jandarov, Roman
Smith, Eric P.
Fugate, Elizabeth
Lindquist, Diana
Markiewski, Maciej M.
Karbowniczek, Magdalena
Wikenheiser-Brokamp, Kathryn A.
Setchell, Kenneth D. R.
McCormack, Francis X.
Xu, Yan
Yu, Jane J.
Upregulation of acid ceramidase contributes to tumor progression in tuberous sclerosis complex
title Upregulation of acid ceramidase contributes to tumor progression in tuberous sclerosis complex
title_full Upregulation of acid ceramidase contributes to tumor progression in tuberous sclerosis complex
title_fullStr Upregulation of acid ceramidase contributes to tumor progression in tuberous sclerosis complex
title_full_unstemmed Upregulation of acid ceramidase contributes to tumor progression in tuberous sclerosis complex
title_short Upregulation of acid ceramidase contributes to tumor progression in tuberous sclerosis complex
title_sort upregulation of acid ceramidase contributes to tumor progression in tuberous sclerosis complex
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10243802/
https://www.ncbi.nlm.nih.gov/pubmed/36927688
http://dx.doi.org/10.1172/jci.insight.166850
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