Drug inhibition of redox factor-1 restores hypoxic-driven changes in Tuberous Sclerosis Complex 2-deficient cells

Champion, Jesse D., Dodd, Kayleigh M., Lam, Hilaire C., Alzahrani, Mohammad A.M., Seifan, Sara, Rad, Ellie, Scourfield, D. Oliver, Fishel, Melissa L., Calver, Brian L., Ager, Ann, Henske, Elizabeth P., Davies, David M., Kelley, Mark R. and Tee, Andrew R. 2022. Drug inhibition of redox factor-1 restores hypoxic-driven changes in Tuberous Sclerosis Complex 2-deficient cells. Cancers

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Abstract

Therapies with mechanistic target of rapamycin complex 1 (mTORC1) inhibitors are not fully curative for Tuberous Sclerosis Complex (TSC) patients. Here we propose that some mTORC1-independent disease facets of TSC involve signaling through redox factor-1 (Ref-1). Ref-1 possesses redox signaling activity that stimulates the transcriptional activity of STAT3, NF-B, and HIF-1 involved in inflammation, proliferation, angiogenesis and hypoxia, respectively. Here we demonstrate that redox signaling through Ref-1 contributes to metabolic transformation and tumor growth in TSC cell model systems. In TSC2-deficient cells, the clinically viable Ref-1 inhibitor, APX3330, was effective at blocking the hyperactivity of STAT3, NF-B, and HIF-1. While Ref-1 inhibitors do not inhibit mTORC1, they potently block cell invasion and vasculature mimicry. Of interest, we show that cell invasion and vasculature mimicry linked to Ref-1 redox signaling are not blocked by mTORC1 inhibitors. Metabolic profiling revealed that Ref-1 inhibitors alter metabolites associated with the glutathione antioxidant pathway as well as metabolites that are heavily dysregulated in TSC2-deficient cells involved in redox homeostasis. Therefore, this work presents Ref-1 and associated redox-regulated transcription factors, such as STAT3, NF-B and HIF-1, as potential therapeutic targets to treat TSC, where targeting these components would likely have additional benefits to just using mTORC1 inhibitors alone.

Item Type:	Article
Schools:	Medicine
Publisher:	MDPI AG
ISSN:	2072-6694
Date of First Compliant Deposit:	14 December 2022
Date of Acceptance:	2 December 2022
Last Modified:	18 Apr 2024 01:05
URI:	https://orca.cardiff.ac.uk/id/eprint/154943

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