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Target Identification of the Marine Natural Products Dictyoceratin-A and -C as Selective Growth Inhibitors in Cancer Cells Adapted to Hypoxic Environments

Hypoxia-adapted cancer cells in tumors contribute to the pathological progression of cancer. The marine spongean sesquiterpene phenols dictyoceratin-A (1) and -C (2) have been shown to induce hypoxia-selective growth inhibition in cultured cancer cells and exhibit in vivo antitumor effects. These co...

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Autores principales: Kawachi, Takashi, Tanaka, Shun, Fukuda, Akinori, Sumii, Yuji, Setiawan, Andi, Kotoku, Naoyuki, Kobayashi, Motomasa, Arai, Masayoshi
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6471994/
https://www.ncbi.nlm.nih.gov/pubmed/30857246
http://dx.doi.org/10.3390/md17030163
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author Kawachi, Takashi
Tanaka, Shun
Fukuda, Akinori
Sumii, Yuji
Setiawan, Andi
Kotoku, Naoyuki
Kobayashi, Motomasa
Arai, Masayoshi
author_facet Kawachi, Takashi
Tanaka, Shun
Fukuda, Akinori
Sumii, Yuji
Setiawan, Andi
Kotoku, Naoyuki
Kobayashi, Motomasa
Arai, Masayoshi
author_sort Kawachi, Takashi
collection PubMed
description Hypoxia-adapted cancer cells in tumors contribute to the pathological progression of cancer. The marine spongean sesquiterpene phenols dictyoceratin-A (1) and -C (2) have been shown to induce hypoxia-selective growth inhibition in cultured cancer cells and exhibit in vivo antitumor effects. These compounds inhibit the accumulation of hypoxia-inducible factor-1α (HIF-1α), which is a drug target in hypoxia-adapted cancer cells, under hypoxic conditions. However, the target molecules of compounds 1 and 2, which are responsible for decreasing HIF-1α expression under hypoxic conditions, remain unclear. In this study, we synthesized probe molecules for compounds 1 and 2 to identify their target molecules and found that both compounds bind to RNA polymerase II-associated protein 3 (RPAP3), which is a component of the R2TP/Prefoldin-like (PEDL) complex. In addition, RPAP3-knockdown cells showed a phenotype similar to that of compound-treated cells.
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spelling pubmed-64719942019-04-27 Target Identification of the Marine Natural Products Dictyoceratin-A and -C as Selective Growth Inhibitors in Cancer Cells Adapted to Hypoxic Environments Kawachi, Takashi Tanaka, Shun Fukuda, Akinori Sumii, Yuji Setiawan, Andi Kotoku, Naoyuki Kobayashi, Motomasa Arai, Masayoshi Mar Drugs Article Hypoxia-adapted cancer cells in tumors contribute to the pathological progression of cancer. The marine spongean sesquiterpene phenols dictyoceratin-A (1) and -C (2) have been shown to induce hypoxia-selective growth inhibition in cultured cancer cells and exhibit in vivo antitumor effects. These compounds inhibit the accumulation of hypoxia-inducible factor-1α (HIF-1α), which is a drug target in hypoxia-adapted cancer cells, under hypoxic conditions. However, the target molecules of compounds 1 and 2, which are responsible for decreasing HIF-1α expression under hypoxic conditions, remain unclear. In this study, we synthesized probe molecules for compounds 1 and 2 to identify their target molecules and found that both compounds bind to RNA polymerase II-associated protein 3 (RPAP3), which is a component of the R2TP/Prefoldin-like (PEDL) complex. In addition, RPAP3-knockdown cells showed a phenotype similar to that of compound-treated cells. MDPI 2019-03-08 /pmc/articles/PMC6471994/ /pubmed/30857246 http://dx.doi.org/10.3390/md17030163 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
Kawachi, Takashi
Tanaka, Shun
Fukuda, Akinori
Sumii, Yuji
Setiawan, Andi
Kotoku, Naoyuki
Kobayashi, Motomasa
Arai, Masayoshi
Target Identification of the Marine Natural Products Dictyoceratin-A and -C as Selective Growth Inhibitors in Cancer Cells Adapted to Hypoxic Environments
title Target Identification of the Marine Natural Products Dictyoceratin-A and -C as Selective Growth Inhibitors in Cancer Cells Adapted to Hypoxic Environments
title_full Target Identification of the Marine Natural Products Dictyoceratin-A and -C as Selective Growth Inhibitors in Cancer Cells Adapted to Hypoxic Environments
title_fullStr Target Identification of the Marine Natural Products Dictyoceratin-A and -C as Selective Growth Inhibitors in Cancer Cells Adapted to Hypoxic Environments
title_full_unstemmed Target Identification of the Marine Natural Products Dictyoceratin-A and -C as Selective Growth Inhibitors in Cancer Cells Adapted to Hypoxic Environments
title_short Target Identification of the Marine Natural Products Dictyoceratin-A and -C as Selective Growth Inhibitors in Cancer Cells Adapted to Hypoxic Environments
title_sort target identification of the marine natural products dictyoceratin-a and -c as selective growth inhibitors in cancer cells adapted to hypoxic environments
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6471994/
https://www.ncbi.nlm.nih.gov/pubmed/30857246
http://dx.doi.org/10.3390/md17030163
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