Champion, Jesse D.Dodd, Kayleigh M.Lam, Hilaire C.Alzahrani, Mohammad A. M.Seifan, SaraRad, EllieScourfield, David OliverFishel, Melissa L.Calver, Brian L.Ager, AnnHenske, Elizabeth P.Davies, David MarkKelley, Mark R.Tee, Andrew R.2023-10-022023-10-022022-12-15Champion JD, Dodd KM, Lam HC, et al. Drug Inhibition of Redox Factor-1 Restores Hypoxia-Driven Changes in Tuberous Sclerosis Complex 2 Deficient Cells. Cancers (Basel). 2022;14(24):6195. Published 2022 Dec 15. doi:10.3390/cancers14246195https://hdl.handle.net/1805/35932Therapies with the 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 a redox signaling activity that stimulates the transcriptional activity of STAT3, NF-kB, and HIF-1α, which are 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-kB, and HIF-1α. 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-kB, and HIF-1α as potential therapeutic targets to treat TSC, where targeting these components would likely have additional benefits compared to using mTORC1 inhibitors alone.en-USAttribution 4.0 InternationalAPE1HIF-1αNF-kBRef-1STAT3TSCAngiogenesisHypoxiamTORRedoxArticle