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Thymoquinone Selectively Kills Hypoxic Renal Cancer Cells by Suppressing HIF-1α-Mediated Glycolysis

Several reports have shown that thymoquinone (TQ) effectively attenuates angiogenesis in cancer cells, resulting in suppression of tumor growth. However, it is not yet clear whether TQ reduces hypoxia-inducible factor-1α (HIF-1α) expression in hypoxic cancer cells. Here, we found that TQ was a novel...

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Autores principales: Lee, Yoon-Mi, Kim, Geon-Hee, Park, Eun-Ji, Oh, Taek-In, Lee, Sujin, Kan, Sang-Yeon, Kang, Hyeji, Kim, Byeong Mo, Kim, Ji Hyung, Lim, Ji-Hong
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6429094/
https://www.ncbi.nlm.nih.gov/pubmed/30832444
http://dx.doi.org/10.3390/ijms20051092
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author Lee, Yoon-Mi
Kim, Geon-Hee
Park, Eun-Ji
Oh, Taek-In
Lee, Sujin
Kan, Sang-Yeon
Kang, Hyeji
Kim, Byeong Mo
Kim, Ji Hyung
Lim, Ji-Hong
author_facet Lee, Yoon-Mi
Kim, Geon-Hee
Park, Eun-Ji
Oh, Taek-In
Lee, Sujin
Kan, Sang-Yeon
Kang, Hyeji
Kim, Byeong Mo
Kim, Ji Hyung
Lim, Ji-Hong
author_sort Lee, Yoon-Mi
collection PubMed
description Several reports have shown that thymoquinone (TQ) effectively attenuates angiogenesis in cancer cells, resulting in suppression of tumor growth. However, it is not yet clear whether TQ reduces hypoxia-inducible factor-1α (HIF-1α) expression in hypoxic cancer cells. Here, we found that TQ was a novel HIF-1α inhibitor through hypoxia response element (HRE)-luciferase assay-based large screening by using 502 natural compounds containing chemical library. TQ reduced HIF-1α protein levels in renal cancer cells; however, it did not affect the HIF-1α protein levels in the presence of proteasome inhibitor, MG132, indicating that the reduction effects of TQ on HIF-1α protein are mediated via the ubiquitination-proteasome dependent pathway. TQ boosted HIF-1α protein degradation, and the mechanism was revealed by inhibiting interaction between HSP90 and HIF-1α. TQ suppressed downstream genes of HIF-1α, indicating negative impact of TQ on HIF-1α transcriptional activities. In addition, TQ altered glucose, lactate, and ATP levels, leading to anaerobic metabolic disturbance. TQ induced apoptosis in hypoxic cancer cells as determined by crystal violet staining and flow cytometry for annexin V-stained cells. Taken together, we suggested that TQ is a potential anticancer agent targeting HIF-1α.
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spelling pubmed-64290942019-04-10 Thymoquinone Selectively Kills Hypoxic Renal Cancer Cells by Suppressing HIF-1α-Mediated Glycolysis Lee, Yoon-Mi Kim, Geon-Hee Park, Eun-Ji Oh, Taek-In Lee, Sujin Kan, Sang-Yeon Kang, Hyeji Kim, Byeong Mo Kim, Ji Hyung Lim, Ji-Hong Int J Mol Sci Article Several reports have shown that thymoquinone (TQ) effectively attenuates angiogenesis in cancer cells, resulting in suppression of tumor growth. However, it is not yet clear whether TQ reduces hypoxia-inducible factor-1α (HIF-1α) expression in hypoxic cancer cells. Here, we found that TQ was a novel HIF-1α inhibitor through hypoxia response element (HRE)-luciferase assay-based large screening by using 502 natural compounds containing chemical library. TQ reduced HIF-1α protein levels in renal cancer cells; however, it did not affect the HIF-1α protein levels in the presence of proteasome inhibitor, MG132, indicating that the reduction effects of TQ on HIF-1α protein are mediated via the ubiquitination-proteasome dependent pathway. TQ boosted HIF-1α protein degradation, and the mechanism was revealed by inhibiting interaction between HSP90 and HIF-1α. TQ suppressed downstream genes of HIF-1α, indicating negative impact of TQ on HIF-1α transcriptional activities. In addition, TQ altered glucose, lactate, and ATP levels, leading to anaerobic metabolic disturbance. TQ induced apoptosis in hypoxic cancer cells as determined by crystal violet staining and flow cytometry for annexin V-stained cells. Taken together, we suggested that TQ is a potential anticancer agent targeting HIF-1α. MDPI 2019-03-03 /pmc/articles/PMC6429094/ /pubmed/30832444 http://dx.doi.org/10.3390/ijms20051092 Text en © 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Lee, Yoon-Mi
Kim, Geon-Hee
Park, Eun-Ji
Oh, Taek-In
Lee, Sujin
Kan, Sang-Yeon
Kang, Hyeji
Kim, Byeong Mo
Kim, Ji Hyung
Lim, Ji-Hong
Thymoquinone Selectively Kills Hypoxic Renal Cancer Cells by Suppressing HIF-1α-Mediated Glycolysis
title Thymoquinone Selectively Kills Hypoxic Renal Cancer Cells by Suppressing HIF-1α-Mediated Glycolysis
title_full Thymoquinone Selectively Kills Hypoxic Renal Cancer Cells by Suppressing HIF-1α-Mediated Glycolysis
title_fullStr Thymoquinone Selectively Kills Hypoxic Renal Cancer Cells by Suppressing HIF-1α-Mediated Glycolysis
title_full_unstemmed Thymoquinone Selectively Kills Hypoxic Renal Cancer Cells by Suppressing HIF-1α-Mediated Glycolysis
title_short Thymoquinone Selectively Kills Hypoxic Renal Cancer Cells by Suppressing HIF-1α-Mediated Glycolysis
title_sort thymoquinone selectively kills hypoxic renal cancer cells by suppressing hif-1α-mediated glycolysis
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6429094/
https://www.ncbi.nlm.nih.gov/pubmed/30832444
http://dx.doi.org/10.3390/ijms20051092
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