Drug Inhibition of Redox Factor-1 Restores Hypoxia-Driven Changes in Tuberous Sclerosis Complex 2 Deficient Cells
Therapies 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 signali...
| Main Authors: | , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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MDPI AG
2022-12-01
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| Series: | Cancers |
| Subjects: | |
| Online Access: | https://www.mdpi.com/2072-6694/14/24/6195 |
| _version_ | 1797461002841751552 |
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| author | Jesse D. Champion Kayleigh M. Dodd Hilaire C. Lam Mohammad A. M. Alzahrani Sara Seifan Ellie Rad David Oliver Scourfield Melissa L. Fishel Brian L. Calver Ann Ager Elizabeth P. Henske David Mark Davies Mark R. Kelley Andrew R. Tee |
| author_facet | Jesse D. Champion Kayleigh M. Dodd Hilaire C. Lam Mohammad A. M. Alzahrani Sara Seifan Ellie Rad David Oliver Scourfield Melissa L. Fishel Brian L. Calver Ann Ager Elizabeth P. Henske David Mark Davies Mark R. Kelley Andrew R. Tee |
| author_sort | Jesse D. Champion |
| collection | DOAJ |
| description | Therapies 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. |
| first_indexed | 2024-03-09T17:14:11Z |
| format | Article |
| id | doaj.art-3bf658cf11574049a9c3079b20859943 |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-09T17:14:11Z |
| publishDate | 2022-12-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-3bf658cf11574049a9c3079b208599432023-11-24T13:47:53ZengMDPI AGCancers2072-66942022-12-011424619510.3390/cancers14246195Drug Inhibition of Redox Factor-1 Restores Hypoxia-Driven Changes in Tuberous Sclerosis Complex 2 Deficient CellsJesse D. Champion0Kayleigh M. Dodd1Hilaire C. Lam2Mohammad A. M. Alzahrani3Sara Seifan4Ellie Rad5David Oliver Scourfield6Melissa L. Fishel7Brian L. Calver8Ann Ager9Elizabeth P. Henske10David Mark Davies11Mark R. Kelley12Andrew R. Tee13Division of Cancer and Genetics, Cardiff University, Heath Park, Cardiff CF14 4XN, UKDivision of Cancer and Genetics, Cardiff University, Heath Park, Cardiff CF14 4XN, UKPulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USADivision of Cancer and Genetics, Cardiff University, Heath Park, Cardiff CF14 4XN, UKDivision of Cancer and Genetics, Cardiff University, Heath Park, Cardiff CF14 4XN, UKDivision of Cancer and Genetics, Cardiff University, Heath Park, Cardiff CF14 4XN, UKDivision of Cancer and Genetics, Cardiff University, Heath Park, Cardiff CF14 4XN, UKHerman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202, USADivision of Cancer and Genetics, Cardiff University, Heath Park, Cardiff CF14 4XN, UKDivision of Infection and Immunity, Cardiff University, Heath Park, Cardiff CF14 4XN, UKPulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USADivision of Cancer and Genetics, Cardiff University, Heath Park, Cardiff CF14 4XN, UKHerman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202, USADivision of Cancer and Genetics, Cardiff University, Heath Park, Cardiff CF14 4XN, UKTherapies 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.https://www.mdpi.com/2072-6694/14/24/6195TSCRef-1APE1mTORHIF-1αSTAT3 |
| spellingShingle | Jesse D. Champion Kayleigh M. Dodd Hilaire C. Lam Mohammad A. M. Alzahrani Sara Seifan Ellie Rad David Oliver Scourfield Melissa L. Fishel Brian L. Calver Ann Ager Elizabeth P. Henske David Mark Davies Mark R. Kelley Andrew R. Tee Drug Inhibition of Redox Factor-1 Restores Hypoxia-Driven Changes in Tuberous Sclerosis Complex 2 Deficient Cells Cancers TSC Ref-1 APE1 mTOR HIF-1α STAT3 |
| title | Drug Inhibition of Redox Factor-1 Restores Hypoxia-Driven Changes in Tuberous Sclerosis Complex 2 Deficient Cells |
| title_full | Drug Inhibition of Redox Factor-1 Restores Hypoxia-Driven Changes in Tuberous Sclerosis Complex 2 Deficient Cells |
| title_fullStr | Drug Inhibition of Redox Factor-1 Restores Hypoxia-Driven Changes in Tuberous Sclerosis Complex 2 Deficient Cells |
| title_full_unstemmed | Drug Inhibition of Redox Factor-1 Restores Hypoxia-Driven Changes in Tuberous Sclerosis Complex 2 Deficient Cells |
| title_short | Drug Inhibition of Redox Factor-1 Restores Hypoxia-Driven Changes in Tuberous Sclerosis Complex 2 Deficient Cells |
| title_sort | drug inhibition of redox factor 1 restores hypoxia driven changes in tuberous sclerosis complex 2 deficient cells |
| topic | TSC Ref-1 APE1 mTOR HIF-1α STAT3 |
| url | https://www.mdpi.com/2072-6694/14/24/6195 |
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