4′,6-Dihydroxy-4-methoxyisoaurone Inhibits the HIF-1α Pathway Through Inhibition of Akt/mTOR/p70S6K/4E-BP1 Phosphorylation
Abstract.: 4′,6-Dihydroxy-4-methoxyisoaurone (ISOA) is an isoaurone compound isolated from Trichosanthes kirilowii seeds, which was identified as an inhibitor of tumor growth. However, the mechanism by which ISOA inhibits hypoxia-inducible factor-1 (HIF-1)-mediated tumor growth is not fully understo...
| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2014-01-01
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| Series: | Journal of Pharmacological Sciences |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S1347861319301422 |
| _version_ | 1819079850062774272 |
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| author | Chunliu Mi Juan Ma Hui Shi Jing Li Fei Wang Jung Joon Lee Xuejun Jin |
| author_facet | Chunliu Mi Juan Ma Hui Shi Jing Li Fei Wang Jung Joon Lee Xuejun Jin |
| author_sort | Chunliu Mi |
| collection | DOAJ |
| description | Abstract.: 4′,6-Dihydroxy-4-methoxyisoaurone (ISOA) is an isoaurone compound isolated from Trichosanthes kirilowii seeds, which was identified as an inhibitor of tumor growth. However, the mechanism by which ISOA inhibits hypoxia-inducible factor-1 (HIF-1)-mediated tumor growth is not fully understood. We here demonstrated the effect of ISOA on HIF-1 activation. ISOA showed a potent inhibitory activity against HIF-1 activation induced by hypoxia in various human cancer cell lines. This compound markedly decreased the hypoxia-induced accumulation of HIF-1α protein dose-dependently, whereas it did not affect the expressions of HIF-1β and topoisomerase-I (Topo-I). Further analysis revealed that the suppression of HIF-1α accumulation by ISOA was closely correlated with strong dephosphorylation of Akt, mammalian target of rapamycin (mTOR), and its effectors ribosomal protein S6 kinase (p70S6K) and eukaryotic initiation factor 4E-binding protein-1 (4E-BP1), a pathway known to regulate HIF-1α expression at the translational level. Furthermore, ISOA prevented hypoxia-induced expression of HIF-1 target genes and suppresses the invasiveness of tumor cells. Taken together, our results suggested that ISOA is an effective inhibitor of HIF-1 through targeting Akt/mTOR/p70S6K/4E-BP1 pathway, thereby, providing new perspectives into the mechanism of its anticancer activity. Keywords:: 4′,6-dihydroxy-4-methoxyisoaurone, HIF-1α, translation, antitumor |
| first_indexed | 2024-12-21T19:35:32Z |
| format | Article |
| id | doaj.art-8a8fbf6faf88401ea6cef5c376be3c74 |
| institution | Directory Open Access Journal |
| issn | 1347-8613 |
| language | English |
| last_indexed | 2024-12-21T19:35:32Z |
| publishDate | 2014-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Journal of Pharmacological Sciences |
| spelling | doaj.art-8a8fbf6faf88401ea6cef5c376be3c742022-12-21T18:52:36ZengElsevierJournal of Pharmacological Sciences1347-86132014-01-0112521932014′,6-Dihydroxy-4-methoxyisoaurone Inhibits the HIF-1α Pathway Through Inhibition of Akt/mTOR/p70S6K/4E-BP1 PhosphorylationChunliu Mi0Juan Ma1Hui Shi2Jing Li3Fei Wang4Jung Joon Lee5Xuejun Jin6Molecular Cancer Research Center, Ministry of Education, College of Pharmacy, Yanbian University, Yanji 133002, Jilin Province, China; Chemical Biology Research Center, Department of Chemistry, Ministry of Education, College of Pharmacy, Yanbian University, Yanji 133002, Jilin Province, ChinaMolecular Cancer Research Center, Ministry of Education, College of Pharmacy, Yanbian University, Yanji 133002, Jilin Province, China; Key Laboratory of Natural Resources of Changbai Mountain & Functional Molecules, Ministry of Education, College of Pharmacy, Yanbian University, Yanji 133002, Jilin Province, ChinaMolecular Cancer Research Center, Ministry of Education, College of Pharmacy, Yanbian University, Yanji 133002, Jilin Province, China; Chemical Biology Research Center, Department of Chemistry, Ministry of Education, College of Pharmacy, Yanbian University, Yanji 133002, Jilin Province, ChinaMolecular Cancer Research Center, Ministry of Education, College of Pharmacy, Yanbian University, Yanji 133002, Jilin Province, China; Chemical Biology Research Center, Department of Chemistry, Ministry of Education, College of Pharmacy, Yanbian University, Yanji 133002, Jilin Province, ChinaMolecular Cancer Research Center, Ministry of Education, College of Pharmacy, Yanbian University, Yanji 133002, Jilin Province, China; Key Laboratory of Natural Resources of Changbai Mountain & Functional Molecules, Ministry of Education, College of Pharmacy, Yanbian University, Yanji 133002, Jilin Province, ChinaMolecular Cancer Research Center, Ministry of Education, College of Pharmacy, Yanbian University, Yanji 133002, Jilin Province, China; Corresponding authors. *ajjlee0908@gmail.com, *bxjjin@ybu.edu.cnMolecular Cancer Research Center, Ministry of Education, College of Pharmacy, Yanbian University, Yanji 133002, Jilin Province, China; Key Laboratory of Natural Resources of Changbai Mountain & Functional Molecules, Ministry of Education, College of Pharmacy, Yanbian University, Yanji 133002, Jilin Province, China; Corresponding authors. *ajjlee0908@gmail.com, *bxjjin@ybu.edu.cnAbstract.: 4′,6-Dihydroxy-4-methoxyisoaurone (ISOA) is an isoaurone compound isolated from Trichosanthes kirilowii seeds, which was identified as an inhibitor of tumor growth. However, the mechanism by which ISOA inhibits hypoxia-inducible factor-1 (HIF-1)-mediated tumor growth is not fully understood. We here demonstrated the effect of ISOA on HIF-1 activation. ISOA showed a potent inhibitory activity against HIF-1 activation induced by hypoxia in various human cancer cell lines. This compound markedly decreased the hypoxia-induced accumulation of HIF-1α protein dose-dependently, whereas it did not affect the expressions of HIF-1β and topoisomerase-I (Topo-I). Further analysis revealed that the suppression of HIF-1α accumulation by ISOA was closely correlated with strong dephosphorylation of Akt, mammalian target of rapamycin (mTOR), and its effectors ribosomal protein S6 kinase (p70S6K) and eukaryotic initiation factor 4E-binding protein-1 (4E-BP1), a pathway known to regulate HIF-1α expression at the translational level. Furthermore, ISOA prevented hypoxia-induced expression of HIF-1 target genes and suppresses the invasiveness of tumor cells. Taken together, our results suggested that ISOA is an effective inhibitor of HIF-1 through targeting Akt/mTOR/p70S6K/4E-BP1 pathway, thereby, providing new perspectives into the mechanism of its anticancer activity. Keywords:: 4′,6-dihydroxy-4-methoxyisoaurone, HIF-1α, translation, antitumorhttp://www.sciencedirect.com/science/article/pii/S1347861319301422 |
| spellingShingle | Chunliu Mi Juan Ma Hui Shi Jing Li Fei Wang Jung Joon Lee Xuejun Jin 4′,6-Dihydroxy-4-methoxyisoaurone Inhibits the HIF-1α Pathway Through Inhibition of Akt/mTOR/p70S6K/4E-BP1 Phosphorylation Journal of Pharmacological Sciences |
| title | 4′,6-Dihydroxy-4-methoxyisoaurone Inhibits the HIF-1α Pathway Through Inhibition of Akt/mTOR/p70S6K/4E-BP1 Phosphorylation |
| title_full | 4′,6-Dihydroxy-4-methoxyisoaurone Inhibits the HIF-1α Pathway Through Inhibition of Akt/mTOR/p70S6K/4E-BP1 Phosphorylation |
| title_fullStr | 4′,6-Dihydroxy-4-methoxyisoaurone Inhibits the HIF-1α Pathway Through Inhibition of Akt/mTOR/p70S6K/4E-BP1 Phosphorylation |
| title_full_unstemmed | 4′,6-Dihydroxy-4-methoxyisoaurone Inhibits the HIF-1α Pathway Through Inhibition of Akt/mTOR/p70S6K/4E-BP1 Phosphorylation |
| title_short | 4′,6-Dihydroxy-4-methoxyisoaurone Inhibits the HIF-1α Pathway Through Inhibition of Akt/mTOR/p70S6K/4E-BP1 Phosphorylation |
| title_sort | 4 6 dihydroxy 4 methoxyisoaurone inhibits the hif 1α pathway through inhibition of akt mtor p70s6k 4e bp1 phosphorylation |
| url | http://www.sciencedirect.com/science/article/pii/S1347861319301422 |
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