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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| Format: | Article |
| Language: | English |
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Nature Portfolio
2017-05-01
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| Series: | Scientific Reports |
| Online Access: | https://doi.org/10.1038/s41598-017-01951-6 |
| _version_ | 1818754186433527808 |
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| 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 |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-12-18T05:19:15Z |
| format | Article |
| id | doaj.art-7e10078120e54867a4813d896b522026 |
| institution | Directory Open Access Journal |
| issn | 2045-2322 |
| language | English |
| last_indexed | 2024-12-18T05:19:15Z |
| publishDate | 2017-05-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj.art-7e10078120e54867a4813d896b5220262022-12-21T21:19:42ZengNature PortfolioScientific Reports2045-23222017-05-017111110.1038/s41598-017-01951-6Stapled BIG3 helical peptide ERAP potentiates anti-tumour activity for breast cancer therapeuticsTetsuro Yoshimaru0Keisuke Aihara1Masato Komatsu2Yosuke Matsushita3Yasumasa Okazaki4Shinya Toyokuni5Junko Honda6Mitsunori Sasa7Yasuo Miyoshi8Akira Otaka9Toyomasa Katagiri10Division of Genome Medicine, Institute for Genome Research, Tokushima UniversityInstitute of Health Biosciences and Graduate School of Pharmaceutical Sciences, Tokushima UniversityDivision of Genome Medicine, Institute for Genome Research, Tokushima UniversityDivision of Genome Medicine, Institute for Genome Research, Tokushima UniversityDepartment of Pathology and Biological Responses, Nagoya University Graduate School of MedicineDepartment of Pathology and Biological Responses, Nagoya University Graduate School of MedicineDepartment of Surgery, National Hospital Organization Higashitokushima Medical CenterDepartment of Surgery, Tokushima Breast Care ClinicDepartment of Surgery, Division of Breast and Endocrine Surgery, Hyogo College of MedicineInstitute of Health Biosciences and Graduate School of Pharmaceutical Sciences, Tokushima UniversityDivision of Genome Medicine, Institute for Genome Research, Tokushima UniversityAbstract 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.https://doi.org/10.1038/s41598-017-01951-6 |
| spellingShingle | 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 Scientific Reports |
| title | 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_short | 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 |
| url | https://doi.org/10.1038/s41598-017-01951-6 |
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