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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-1\u03b1, 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-1\u03b1. 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-1\u03b1 as potential therapeutic targets to treat TSC, where targeting these components would likely have additional benefits compared to using mTORC1 inhibitors alone.<\/jats:p>","DOI":"10.3390\/cancers14246195","type":"journal-article","created":{"date-parts":[[2022,12,16]],"date-time":"2022-12-16T02:54:02Z","timestamp":1671159242000},"page":"6195","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Drug Inhibition of Redox Factor-1 Restores Hypoxia-Driven Changes in Tuberous Sclerosis Complex 2 Deficient Cells"],"prefix":"10.3390","volume":"14","author":[{"given":"Jesse D.","family":"Champion","sequence":"first","affiliation":[{"name":"Division of Cancer and Genetics, Cardiff University, Heath Park, Cardiff CF14 4XN, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kayleigh M.","family":"Dodd","sequence":"additional","affiliation":[{"name":"Division of Cancer and Genetics, Cardiff University, Heath Park, Cardiff CF14 4XN, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hilaire C.","family":"Lam","sequence":"additional","affiliation":[{"name":"Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women\u2019s Hospital, Harvard Medical School, Boston, MA 02115, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohammad A. M.","family":"Alzahrani","sequence":"additional","affiliation":[{"name":"Division of Cancer and Genetics, Cardiff University, Heath Park, Cardiff CF14 4XN, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sara","family":"Seifan","sequence":"additional","affiliation":[{"name":"Division of Cancer and Genetics, Cardiff University, Heath Park, Cardiff CF14 4XN, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ellie","family":"Rad","sequence":"additional","affiliation":[{"name":"Division of Cancer and Genetics, Cardiff University, Heath Park, Cardiff CF14 4XN, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David Oliver","family":"Scourfield","sequence":"additional","affiliation":[{"name":"Division of Cancer and Genetics, Cardiff University, Heath Park, Cardiff CF14 4XN, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Melissa L.","family":"Fishel","sequence":"additional","affiliation":[{"name":"Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brian L.","family":"Calver","sequence":"additional","affiliation":[{"name":"Division of Cancer and Genetics, Cardiff University, Heath Park, Cardiff CF14 4XN, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5763-8908","authenticated-orcid":false,"given":"Ann","family":"Ager","sequence":"additional","affiliation":[{"name":"Division of Infection and Immunity, Cardiff University, Heath Park, Cardiff CF14 4XN, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elizabeth P.","family":"Henske","sequence":"additional","affiliation":[{"name":"Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women\u2019s Hospital, Harvard Medical School, Boston, MA 02115, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David Mark","family":"Davies","sequence":"additional","affiliation":[{"name":"Division of Cancer and Genetics, Cardiff University, Heath Park, Cardiff CF14 4XN, UK"},{"name":"Department of Oncology, South West Wales Cancer Centre, Singleton Hospital, Swansea SA2 8QA, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9472-1826","authenticated-orcid":false,"given":"Mark R.","family":"Kelley","sequence":"additional","affiliation":[{"name":"Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5577-4631","authenticated-orcid":false,"given":"Andrew R.","family":"Tee","sequence":"additional","affiliation":[{"name":"Division of Cancer and Genetics, Cardiff University, Heath Park, Cardiff CF14 4XN, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,12,15]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1016\/bs.adgen.2018.11.003","article-title":"Finding a cure for tuberous sclerosis complex: From genetics through to targeted drug therapies","volume":"Volume 103","author":"Kumar","year":"2019","journal-title":"Advances in Genetics"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"16035","DOI":"10.1038\/nrdp.2016.35","article-title":"Tuberous sclerosis complex","volume":"2","author":"Henske","year":"2016","journal-title":"Nat. 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