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Efficacy of Dual Inhibition of Glycolysis and Glutaminolysis for Therapy of Renal Lesions in Tsc2(+/−) Mice()
Tuberous sclerosis is caused by mutations in the TSC1 or TSC2 gene and characterized by development of tumors in multiple organs including the kidneys. TSC-associated tumors exhibit somatic loss of the second allele of the TSC genes, leading to aberrant activation of the mechanistic target of rapamy...
Autores principales: | , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Neoplasia Press
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6324218/ https://www.ncbi.nlm.nih.gov/pubmed/30622053 http://dx.doi.org/10.1016/j.neo.2018.12.003 |
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author | Jones, Ashley T. Narov, Kalin Yang, Jian Sampson, Julian R. Shen, Ming Hong |
author_facet | Jones, Ashley T. Narov, Kalin Yang, Jian Sampson, Julian R. Shen, Ming Hong |
author_sort | Jones, Ashley T. |
collection | PubMed |
description | Tuberous sclerosis is caused by mutations in the TSC1 or TSC2 gene and characterized by development of tumors in multiple organs including the kidneys. TSC-associated tumors exhibit somatic loss of the second allele of the TSC genes, leading to aberrant activation of the mechanistic target of rapamycin (mTOR) signaling pathway. Activation of mTOR complex 1 (mTORC1) causes addiction to glucose and glutamine in Tsc1(−/−)or Tsc2(−/−) mouse embryonic fibroblasts (MEFs). Blocking of glutamine anaplerosis in combination with glycolytic inhibition causes significant cell death in Tsc2(−/−) but not Tsc2(+/+) MEFs. In this study, we tested efficacy of dual inhibition of glycolysis with 3-BrPA and glutaminolysis with CB-839 for renal tumors in Tsc2(+/−) mice. Following 2 months of treatment of Tsc2(+/−) mice from the age of 12 months, combination of 3-BrPA and CB-839 significantly reduced overall size and cellular areas of all renal lesions (cystic/papillary adenomas and solid carcinomas), but neither alone did. Combination of 3-BrPA and CB-839 inhibited mTORC1 and the proliferation of tumor cells but did not increase apoptosis. However, combination of 3-BrPA and CB-839 was not as efficacious as rapamycin alone or rapamycin in combination with either 3-BrPA or CB-839 for renal lesions of Tsc2(+/−) mice. Consistently, rapamycin alone or rapamycin in combination with either 3-BrPA or CB-839 had stronger inhibitory effects on mTORC1 and proliferation of tumor cells than combination of 3-BrPA and CB-839. We conclude that combination of 3-BRPA and CB-839 may not offer a better therapeutic strategy than rapamycin for TSC-associated tumors. |
format | Online Article Text |
id | pubmed-6324218 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | Neoplasia Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-63242182019-02-22 Efficacy of Dual Inhibition of Glycolysis and Glutaminolysis for Therapy of Renal Lesions in Tsc2(+/−) Mice() Jones, Ashley T. Narov, Kalin Yang, Jian Sampson, Julian R. Shen, Ming Hong Neoplasia Original article Tuberous sclerosis is caused by mutations in the TSC1 or TSC2 gene and characterized by development of tumors in multiple organs including the kidneys. TSC-associated tumors exhibit somatic loss of the second allele of the TSC genes, leading to aberrant activation of the mechanistic target of rapamycin (mTOR) signaling pathway. Activation of mTOR complex 1 (mTORC1) causes addiction to glucose and glutamine in Tsc1(−/−)or Tsc2(−/−) mouse embryonic fibroblasts (MEFs). Blocking of glutamine anaplerosis in combination with glycolytic inhibition causes significant cell death in Tsc2(−/−) but not Tsc2(+/+) MEFs. In this study, we tested efficacy of dual inhibition of glycolysis with 3-BrPA and glutaminolysis with CB-839 for renal tumors in Tsc2(+/−) mice. Following 2 months of treatment of Tsc2(+/−) mice from the age of 12 months, combination of 3-BrPA and CB-839 significantly reduced overall size and cellular areas of all renal lesions (cystic/papillary adenomas and solid carcinomas), but neither alone did. Combination of 3-BrPA and CB-839 inhibited mTORC1 and the proliferation of tumor cells but did not increase apoptosis. However, combination of 3-BrPA and CB-839 was not as efficacious as rapamycin alone or rapamycin in combination with either 3-BrPA or CB-839 for renal lesions of Tsc2(+/−) mice. Consistently, rapamycin alone or rapamycin in combination with either 3-BrPA or CB-839 had stronger inhibitory effects on mTORC1 and proliferation of tumor cells than combination of 3-BrPA and CB-839. We conclude that combination of 3-BRPA and CB-839 may not offer a better therapeutic strategy than rapamycin for TSC-associated tumors. Neoplasia Press 2019-01-08 /pmc/articles/PMC6324218/ /pubmed/30622053 http://dx.doi.org/10.1016/j.neo.2018.12.003 Text en © 2018 The Authors http://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). |
spellingShingle | Original article Jones, Ashley T. Narov, Kalin Yang, Jian Sampson, Julian R. Shen, Ming Hong Efficacy of Dual Inhibition of Glycolysis and Glutaminolysis for Therapy of Renal Lesions in Tsc2(+/−) Mice() |
title | Efficacy of Dual Inhibition of Glycolysis and Glutaminolysis for Therapy of Renal Lesions in Tsc2(+/−) Mice() |
title_full | Efficacy of Dual Inhibition of Glycolysis and Glutaminolysis for Therapy of Renal Lesions in Tsc2(+/−) Mice() |
title_fullStr | Efficacy of Dual Inhibition of Glycolysis and Glutaminolysis for Therapy of Renal Lesions in Tsc2(+/−) Mice() |
title_full_unstemmed | Efficacy of Dual Inhibition of Glycolysis and Glutaminolysis for Therapy of Renal Lesions in Tsc2(+/−) Mice() |
title_short | Efficacy of Dual Inhibition of Glycolysis and Glutaminolysis for Therapy of Renal Lesions in Tsc2(+/−) Mice() |
title_sort | efficacy of dual inhibition of glycolysis and glutaminolysis for therapy of renal lesions in tsc2(+/−) mice() |
topic | Original article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6324218/ https://www.ncbi.nlm.nih.gov/pubmed/30622053 http://dx.doi.org/10.1016/j.neo.2018.12.003 |
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