BHMPS Inhibits Breast Cancer Migration and Invasion by Disrupting Rab27a-Mediated EGFR and Fibronectin Secretion
Our previous work demonstrated that (<i>E</i>)-<i>N</i>-benzyl-6-(2-(3, 4-dihydroxybenzylidene) hydrazinyl)-<i>N</i>-methylpyridine-3-sulfonamide (BHMPS), a novel synthetic inhibitor of Rab27aSlp(s) interaction, suppresses tumor cell invasion and metastasis. Here,...
| Main Authors: | , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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MDPI AG
2022-01-01
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| Series: | Cancers |
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| Online Access: | https://www.mdpi.com/2072-6694/14/2/373 |
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| author | Jeong-In Park Kyung-Hee Song Seong-Mook Kang Jeeyong Lee Seong-Jun Cho Hyun Kyung Choi Jiyeon Ahn Jong-Kuk Park Jaesung Kim Sang-Gu Hwang Dae-Seog Lim Joon Kim Seung-Youn Jung Jie-Young Song |
| author_facet | Jeong-In Park Kyung-Hee Song Seong-Mook Kang Jeeyong Lee Seong-Jun Cho Hyun Kyung Choi Jiyeon Ahn Jong-Kuk Park Jaesung Kim Sang-Gu Hwang Dae-Seog Lim Joon Kim Seung-Youn Jung Jie-Young Song |
| author_sort | Jeong-In Park |
| collection | DOAJ |
| description | Our previous work demonstrated that (<i>E</i>)-<i>N</i>-benzyl-6-(2-(3, 4-dihydroxybenzylidene) hydrazinyl)-<i>N</i>-methylpyridine-3-sulfonamide (BHMPS), a novel synthetic inhibitor of Rab27aSlp(s) interaction, suppresses tumor cell invasion and metastasis. Here, we aimed to further investigate the mechanisms of action and biological significance of BHMPS. BHMPS decreased the expression of epithelial-mesenchymal transition transcription factors through inhibition of focal adhesion kinase and c-Jun N-terminal kinase activation, thereby reducing the migration and invasion of breast cancer. Additionally, knockdown of Rab27a inhibited tumor migration, with changes in related signaling molecules, whereas overexpression of Rab27a reversed this phenomenon. BHMPS effectively prevented the interaction of Rab27a and its effector Slp4, which was verified by co-localization, immunoprecipitation, and in situ proximity ligation assays. BHMPS decreased the secretion of epidermal growth factor receptor and fibronectin by interfering with vesicle trafficking, as indicated by increased perinuclear accumulation of CD63-positive vesicles. Moreover, administration of BHMPS suppressed tumor growth in Rab27a-overexpressing MDA-MB-231 xenograft mice. These findings suggest that BHMPS may be a promising candidate for attenuating tumor migration and invasion by blocking Rab27a-mediated exocytosis. |
| first_indexed | 2024-03-10T01:46:10Z |
| format | Article |
| id | doaj.art-64825df2ffdf4323ab6eea31d783f1ad |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-10T01:46:10Z |
| publishDate | 2022-01-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-64825df2ffdf4323ab6eea31d783f1ad2023-11-23T13:13:54ZengMDPI AGCancers2072-66942022-01-0114237310.3390/cancers14020373BHMPS Inhibits Breast Cancer Migration and Invasion by Disrupting Rab27a-Mediated EGFR and Fibronectin SecretionJeong-In Park0Kyung-Hee Song1Seong-Mook Kang2Jeeyong Lee3Seong-Jun Cho4Hyun Kyung Choi5Jiyeon Ahn6Jong-Kuk Park7Jaesung Kim8Sang-Gu Hwang9Dae-Seog Lim10Joon Kim11Seung-Youn Jung12Jie-Young Song13Division of Radiation Biomedical Research, Korea Institute of Radiological & Medical Sciences, Seoul 01812, KoreaDivision of Radiation Biomedical Research, Korea Institute of Radiological & Medical Sciences, Seoul 01812, KoreaDivision of Radiation Biomedical Research, Korea Institute of Radiological & Medical Sciences, Seoul 01812, KoreaDivision of Radiation Biomedical Research, Korea Institute of Radiological & Medical Sciences, Seoul 01812, KoreaLow-dose Radiation Research Team, Radiation Health Institute, Korea Hydro & Nuclear Power Co., Ltd., Seoul 01450, KoreaDepartment of Chemistry, Sogang University, Seoul 04107, KoreaDivision of Radiation Biomedical Research, Korea Institute of Radiological & Medical Sciences, Seoul 01812, KoreaDivision of Radiation Biomedical Research, Korea Institute of Radiological & Medical Sciences, Seoul 01812, KoreaDivision of Radiation Biomedical Research, Korea Institute of Radiological & Medical Sciences, Seoul 01812, KoreaDivision of Radiation Biomedical Research, Korea Institute of Radiological & Medical Sciences, Seoul 01812, KoreaDepartment of Biotechnology, CHA University, Seongnam 13488, Gyeonggi-do, KoreaLaboratory of Biochemistry, Division of Life Sciences, Korea University, Seoul 02841, KoreaDivision of Radiation Biomedical Research, Korea Institute of Radiological & Medical Sciences, Seoul 01812, KoreaDivision of Radiation Biomedical Research, Korea Institute of Radiological & Medical Sciences, Seoul 01812, KoreaOur previous work demonstrated that (<i>E</i>)-<i>N</i>-benzyl-6-(2-(3, 4-dihydroxybenzylidene) hydrazinyl)-<i>N</i>-methylpyridine-3-sulfonamide (BHMPS), a novel synthetic inhibitor of Rab27aSlp(s) interaction, suppresses tumor cell invasion and metastasis. Here, we aimed to further investigate the mechanisms of action and biological significance of BHMPS. BHMPS decreased the expression of epithelial-mesenchymal transition transcription factors through inhibition of focal adhesion kinase and c-Jun N-terminal kinase activation, thereby reducing the migration and invasion of breast cancer. Additionally, knockdown of Rab27a inhibited tumor migration, with changes in related signaling molecules, whereas overexpression of Rab27a reversed this phenomenon. BHMPS effectively prevented the interaction of Rab27a and its effector Slp4, which was verified by co-localization, immunoprecipitation, and in situ proximity ligation assays. BHMPS decreased the secretion of epidermal growth factor receptor and fibronectin by interfering with vesicle trafficking, as indicated by increased perinuclear accumulation of CD63-positive vesicles. Moreover, administration of BHMPS suppressed tumor growth in Rab27a-overexpressing MDA-MB-231 xenograft mice. These findings suggest that BHMPS may be a promising candidate for attenuating tumor migration and invasion by blocking Rab27a-mediated exocytosis.https://www.mdpi.com/2072-6694/14/2/373Rab GTPaseinvasionmigrationvesicle traffickingbreast cancer |
| spellingShingle | Jeong-In Park Kyung-Hee Song Seong-Mook Kang Jeeyong Lee Seong-Jun Cho Hyun Kyung Choi Jiyeon Ahn Jong-Kuk Park Jaesung Kim Sang-Gu Hwang Dae-Seog Lim Joon Kim Seung-Youn Jung Jie-Young Song BHMPS Inhibits Breast Cancer Migration and Invasion by Disrupting Rab27a-Mediated EGFR and Fibronectin Secretion Cancers Rab GTPase invasion migration vesicle trafficking breast cancer |
| title | BHMPS Inhibits Breast Cancer Migration and Invasion by Disrupting Rab27a-Mediated EGFR and Fibronectin Secretion |
| title_full | BHMPS Inhibits Breast Cancer Migration and Invasion by Disrupting Rab27a-Mediated EGFR and Fibronectin Secretion |
| title_fullStr | BHMPS Inhibits Breast Cancer Migration and Invasion by Disrupting Rab27a-Mediated EGFR and Fibronectin Secretion |
| title_full_unstemmed | BHMPS Inhibits Breast Cancer Migration and Invasion by Disrupting Rab27a-Mediated EGFR and Fibronectin Secretion |
| title_short | BHMPS Inhibits Breast Cancer Migration and Invasion by Disrupting Rab27a-Mediated EGFR and Fibronectin Secretion |
| title_sort | bhmps inhibits breast cancer migration and invasion by disrupting rab27a mediated egfr and fibronectin secretion |
| topic | Rab GTPase invasion migration vesicle trafficking breast cancer |
| url | https://www.mdpi.com/2072-6694/14/2/373 |
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