Efficacy of dual inhibition of glycolysis and glutaminolysis for therapy of renal lesions in Tsc2+/− Mice1

Jones, Ashley T., Narov, Kalin, Yang, Jian ORCID: https://orcid.org/0000-0003-2631-4553, Sampson, Julian R. ORCID: https://orcid.org/0000-0002-2902-2348 and Shen, Ming Hong ORCID: https://orcid.org/0000-0002-3891-7231 2019. Efficacy of dual inhibition of glycolysis and glutaminolysis for therapy of renal lesions in Tsc2+/− Mice1. NEOPLASIA 21 (2) , pp. 230-238. 10.1016/j.neo.2018.12.003

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Abstract

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.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Medicine
Publisher:	Elsevier
ISSN:	1522-8002
Date of First Compliant Deposit:	10 January 2019
Date of Acceptance:	13 December 2018
Last Modified:	18 May 2023 02:10
URI:	https://orca.cardiff.ac.uk/id/eprint/118284

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