Stapled BIG3 helical peptide ERAP potentiates anti-tumour activity for breast cancer therapeutics

Abstract Estradiol (E2) and the oestrogen receptor-alpha (ERα) signalling pathway play pivotal roles in the proliferative activity of breast cancer cells. Recent findings show that the brefeldin A-inhibited guanine nucleotide-exchange protein 3-prohibitin 2 (BIG3-PHB2) complex plays a crucial role i...

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Autores principales:	Tetsuro Yoshimaru, Keisuke Aihara, Masato Komatsu, Yosuke Matsushita, Yasumasa Okazaki, Shinya Toyokuni, Junko Honda, Mitsunori Sasa, Yasuo Miyoshi, Akira Otaka, Toyomasa Katagiri
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/7e10078120e54867a4813d896b522026
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spelling	oai:doaj.org-article:7e10078120e54867a4813d896b5220262021-12-02T11:40:21ZStapled BIG3 helical peptide ERAP potentiates anti-tumour activity for breast cancer therapeutics10.1038/s41598-017-01951-62045-2322https://doaj.org/article/7e10078120e54867a4813d896b5220262017-05-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-01951-6https://doaj.org/toc/2045-2322Abstract Estradiol (E2) and the oestrogen receptor-alpha (ERα) signalling pathway play pivotal roles in the proliferative activity of breast cancer cells. Recent findings show that the brefeldin A-inhibited guanine nucleotide-exchange protein 3-prohibitin 2 (BIG3-PHB2) complex plays a crucial role in E2/ERα signalling modulation in breast cancer cells. Moreover, specific inhibition of the BIG3-PHB2 interaction using the ERα activity-regulator synthetic peptide (ERAP: 165–177 amino acids), derived from α-helical BIG3 sequence, resulted in a significant anti-tumour effect. However, the duration of this effect was very short for viable clinical application. We developed the chemically modified ERAP using stapling methods (stapledERAP) to improve the duration of its antitumour effects. The stapledERAP specifically inhibited the BIG3-PHB2 interaction and exhibited long-lasting suppressive activity. Its intracellular localization without the membrane-permeable polyarginine sequence was possible via the formation of a stable α-helix structure by stapling. Tumour bearing-mice treated daily or weekly with stapledERAP effectively prevented the BIG3-PHB2 interaction, leading to complete regression of E2-dependent tumours in vivo. Most importantly, combination of stapledERAP with tamoxifen, fulvestrant, and everolimus caused synergistic inhibitory effects on growth of breast cancer cells. Our findings suggested that the stapled ERAP may be a promising anti-tumour drug to suppress luminal-type breast cancer growth.Tetsuro YoshimaruKeisuke AiharaMasato KomatsuYosuke MatsushitaYasumasa OkazakiShinya ToyokuniJunko HondaMitsunori SasaYasuo MiyoshiAkira OtakaToyomasa KatagiriNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-11 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Tetsuro Yoshimaru Keisuke Aihara Masato Komatsu Yosuke Matsushita Yasumasa Okazaki Shinya Toyokuni Junko Honda Mitsunori Sasa Yasuo Miyoshi Akira Otaka Toyomasa Katagiri Stapled BIG3 helical peptide ERAP potentiates anti-tumour activity for breast cancer therapeutics
description	Abstract Estradiol (E2) and the oestrogen receptor-alpha (ERα) signalling pathway play pivotal roles in the proliferative activity of breast cancer cells. Recent findings show that the brefeldin A-inhibited guanine nucleotide-exchange protein 3-prohibitin 2 (BIG3-PHB2) complex plays a crucial role in E2/ERα signalling modulation in breast cancer cells. Moreover, specific inhibition of the BIG3-PHB2 interaction using the ERα activity-regulator synthetic peptide (ERAP: 165–177 amino acids), derived from α-helical BIG3 sequence, resulted in a significant anti-tumour effect. However, the duration of this effect was very short for viable clinical application. We developed the chemically modified ERAP using stapling methods (stapledERAP) to improve the duration of its antitumour effects. The stapledERAP specifically inhibited the BIG3-PHB2 interaction and exhibited long-lasting suppressive activity. Its intracellular localization without the membrane-permeable polyarginine sequence was possible via the formation of a stable α-helix structure by stapling. Tumour bearing-mice treated daily or weekly with stapledERAP effectively prevented the BIG3-PHB2 interaction, leading to complete regression of E2-dependent tumours in vivo. Most importantly, combination of stapledERAP with tamoxifen, fulvestrant, and everolimus caused synergistic inhibitory effects on growth of breast cancer cells. Our findings suggested that the stapled ERAP may be a promising anti-tumour drug to suppress luminal-type breast cancer growth.
format	article
author	Tetsuro Yoshimaru Keisuke Aihara Masato Komatsu Yosuke Matsushita Yasumasa Okazaki Shinya Toyokuni Junko Honda Mitsunori Sasa Yasuo Miyoshi Akira Otaka Toyomasa Katagiri
author_facet	Tetsuro Yoshimaru Keisuke Aihara Masato Komatsu Yosuke Matsushita Yasumasa Okazaki Shinya Toyokuni Junko Honda Mitsunori Sasa Yasuo Miyoshi Akira Otaka Toyomasa Katagiri
author_sort	Tetsuro Yoshimaru
title	Stapled BIG3 helical peptide ERAP potentiates anti-tumour activity for breast cancer therapeutics
title_short	Stapled BIG3 helical peptide ERAP potentiates anti-tumour activity for breast cancer therapeutics
title_full	Stapled BIG3 helical peptide ERAP potentiates anti-tumour activity for breast cancer therapeutics
title_fullStr	Stapled BIG3 helical peptide ERAP potentiates anti-tumour activity for breast cancer therapeutics
title_full_unstemmed	Stapled BIG3 helical peptide ERAP potentiates anti-tumour activity for breast cancer therapeutics
title_sort	stapled big3 helical peptide erap potentiates anti-tumour activity for breast cancer therapeutics
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/7e10078120e54867a4813d896b522026
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Stapled BIG3 helical peptide ERAP potentiates anti-tumour activity for breast cancer therapeutics

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