{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T10:14:18Z","timestamp":1785406458203,"version":"3.56.0"},"reference-count":58,"publisher":"MDPI AG","issue":"13","license":[{"start":{"date-parts":[[2026,6,23]],"date-time":"2026-06-23T00:00:00Z","timestamp":1782172800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Grant-in-Aid for Scientific Research","award":["23K06139"],"award-info":[{"award-number":["23K06139"]}]},{"DOI":"10.13039\/100018501","name":"Cancer Research Institute, Kanazawa University","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100018501","id-type":"DOI","asserted-by":"crossref"}]},{"id":[{"id":"https:\/\/ror.org\/02hwp6a56","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Heparanase 1 (HPSE1) is the only mammalian endoglycosidase that cleaves heparan sulfate (HS), a glycosaminoglycan (GAG), and is frequently upregulated in cancers, thereby promoting tumor progression. Despite extensive efforts to develop inhibitors of its HS-degrading activity, its non-enzymatic functions limit therapeutic efficacy and pose a major challenge for therapeutic development. Thus, inhibiting HPSE1 expression is critical for controlling its enzymatic and non-enzymatic functions; however, no FDA-approved inhibitors are currently available. Here, we identify auranofin (AUF), an oral gold-containing drug used to treat rheumatoid arthritis, as a potent inhibitor of HPSE1 promoter activity. High-throughput screening revealed that an atypical protein kinase C (aPKC)\u2013NF-\u03baB signaling axis is a key regulator of HPSE1 expression. Notably, AUF treatment reduced HPSE1 expression and significantly suppressed the invasive capacity of MDA-MB-231 cells in a Transwell migration assay. We then investigated the role of HPSE1 in the invasive activity of MDA-MB-231 cells, which produce higher levels of hyaluronan (HA) and HS than non-invasive cells. Neither HS degradation, HA supplementation in Matrigel during Transwell migration, nor HPSE1 overexpression alone was sufficient to drive invasion, suggesting that invasive capacity depends on mesenchymal features and coordinated induction of HPSE1 and GAGs rather than HS degradation. Collectively, our findings demonstrate that AUF-mediated inhibition of aPKC suppresses HPSE1 expression, thereby inhibiting both its enzymatic and non-enzymatic functions and limiting cancer progression, metastasis, and angiogenesis. These results highlight the therapeutic potential of AUF for targeting HPSE1-driven tumor progression and support its repurposing for cancer treatment.<\/jats:p>","DOI":"10.3390\/ijms27135646","type":"journal-article","created":{"date-parts":[[2026,6,24]],"date-time":"2026-06-24T03:09:17Z","timestamp":1782270557000},"page":"5646","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Auranofin Suppresses Cancer Cell Invasion by Inhibiting Heparanase-1 Expression via the aPKC\u2013NF-\u03baB Pathway"],"prefix":"10.3390","volume":"27","author":[{"given":"Masahiro","family":"Komeno","sequence":"first","affiliation":[{"name":"Faculty of Pharmaceutical Sciences, Tokyo University of Science, 6-3-1 Niijyuku, Katsushika, Tokyo 125-8585, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rin","family":"Miyajima","sequence":"additional","affiliation":[{"name":"Faculty of Pharmaceutical Sciences, Tokyo University of Science, 6-3-1 Niijyuku, Katsushika, Tokyo 125-8585, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kanami","family":"Miyashita","sequence":"additional","affiliation":[{"name":"Faculty of Pharmaceutical Sciences, Tokyo University of Science, 6-3-1 Niijyuku, Katsushika, Tokyo 125-8585, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masato","family":"Suzuki","sequence":"additional","affiliation":[{"name":"Faculty of Pharmaceutical Sciences, Tokyo University of Science, 6-3-1 Niijyuku, Katsushika, Tokyo 125-8585, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Toshinao","family":"Matoba","sequence":"additional","affiliation":[{"name":"Faculty of Pharmaceutical Sciences, Tokyo University of Science, 6-3-1 Niijyuku, Katsushika, Tokyo 125-8585, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ayuna","family":"Miwa","sequence":"additional","affiliation":[{"name":"Faculty of Pharmaceutical Sciences, Tokyo University of Science, 6-3-1 Niijyuku, Katsushika, Tokyo 125-8585, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shoo","family":"Katsumoto","sequence":"additional","affiliation":[{"name":"Faculty of Pharmaceutical Sciences, Tokyo University of Science, 6-3-1 Niijyuku, Katsushika, Tokyo 125-8585, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ryosuke","family":"Yasumura","sequence":"additional","affiliation":[{"name":"Faculty of Pharmaceutical Sciences, Tokyo University of Science, 6-3-1 Niijyuku, Katsushika, Tokyo 125-8585, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kenta","family":"Ko","sequence":"additional","affiliation":[{"name":"Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8675, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hitoshi","family":"Kotani","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, Shimane University, Izumo 693-8501, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-3657-2043","authenticated-orcid":false,"given":"Shoma","family":"Tamori","sequence":"additional","affiliation":[{"name":"Faculty of Pharmaceutical Sciences, Tokyo University of Science, 6-3-1 Niijyuku, Katsushika, Tokyo 125-8585, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-9798-5085","authenticated-orcid":false,"given":"Shoko","family":"Itakura","sequence":"additional","affiliation":[{"name":"Faculty of Pharmaceutical Sciences, Tokyo University of Science, 6-3-1 Niijyuku, Katsushika, Tokyo 125-8585, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2065-6122","authenticated-orcid":false,"given":"Kosuke","family":"Kusamori","sequence":"additional","affiliation":[{"name":"Faculty of Pharmaceutical Sciences, Tokyo University of Science, 6-3-1 Niijyuku, Katsushika, Tokyo 125-8585, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3295-5130","authenticated-orcid":false,"given":"Makiya","family":"Nishikawa","sequence":"additional","affiliation":[{"name":"Faculty of Pharmaceutical Sciences, Tokyo University of Science, 6-3-1 Niijyuku, Katsushika, Tokyo 125-8585, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kazunori","family":"Akimoto","sequence":"additional","affiliation":[{"name":"Faculty of Pharmaceutical Sciences, Tokyo University of Science, 6-3-1 Niijyuku, Katsushika, Tokyo 125-8585, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takashi","family":"Suda","sequence":"additional","affiliation":[{"name":"Cancer Research Institute, Kanazawa University, Kakuma-machi, Kanazawa 920-1192, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chiaki","family":"Takahashi","sequence":"additional","affiliation":[{"name":"Cancer Research Institute, Kanazawa University, Kakuma-machi, Kanazawa 920-1192, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6803-6147","authenticated-orcid":false,"given":"Nobuaki","family":"Higashi","sequence":"additional","affiliation":[{"name":"School of Pharmacy and Pharmaceutical Sciences, Hoshi University, 2-4-41, Ebara, Shinagawa-ku, Tokyo 142-8501, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2803-3704","authenticated-orcid":false,"given":"Fuming","family":"Zhang","sequence":"additional","affiliation":[{"name":"Center for Biotechnology and Interdisciplinary Studies, Rensselaer Polytechnic Institute, 110 8th Street, Troy, NY 12180, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Toshihiko","family":"Toida","sequence":"additional","affiliation":[{"name":"Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8675, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2622-4825","authenticated-orcid":false,"given":"Kyohei","family":"Higashi","sequence":"additional","affiliation":[{"name":"Faculty of Pharmaceutical Sciences, Tokyo University of Science, 6-3-1 Niijyuku, Katsushika, Tokyo 125-8585, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,6,23]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"453","DOI":"10.1186\/s12967-020-02624-1","article-title":"Heparanase and the hallmarks of cancer","volume":"18","author":"Jayatilleke","year":"2020","journal-title":"J. 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