Targeting hyaluronan-mediated motility receptor (HMMR) enhances response to androgen receptor signalling inhibitors in prostate cancer

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dc.contributor.authorHinneh, J.A.
dc.contributor.authorGillis, J.L.
dc.contributor.authorMah, C.Y.
dc.contributor.authorIrani, S.
dc.contributor.authorShrestha, R.K.
dc.contributor.authorRyan, N.K.
dc.contributor.authorAtsushi, E.
dc.contributor.authorNassar, Z.D.
dc.contributor.authorLynn, D.J.
dc.contributor.authorSelth, L.A.
dc.contributor.authorKato, M.
dc.contributor.authorCentenera, M.M.
dc.contributor.authorButler, L.M.
dc.date.issued2023
dc.descriptionPublished online: 6 September 2023
dc.description.abstractBACKGROUND: Resistance to androgen receptor signalling inhibitors (ARSIs) represents a major clinical challenge in prostate cancer. We previously demonstrated that the ARSI enzalutamide inhibits only a subset of all AR-regulated genes, and hypothesise that the unaffected gene networks represent potential targets for therapeutic intervention. This study identified the hyaluronan-mediated motility receptor (HMMR) as a survival factor in prostate cancer and investigated its potential as a co-target for overcoming resistance to ARSIs. METHODS: RNA-seq, RT-qPCR and Western Blot were used to evaluate the regulation of HMMR by AR and ARSIs. HMMR inhibition was achieved via siRNA knockdown or pharmacological inhibition using 4-methylumbelliferone (4-MU) in prostate cancer cell lines, a mouse xenograft model and patient-derived explants (PDEs). RESULTS: HMMR was an AR-regulated factor that was unaffected by ARSIs. Genetic (siRNA) or pharmacological (4-MU) inhibition of HMMR significantly suppressed growth and induced apoptosis in hormone-sensitive and enzalutamide-resistant models of prostate cancer. Mechanistically, 4-MU inhibited AR nuclear translocation, AR protein expression and subsequent downstream AR signalling. 4-MU enhanced the growth-suppressive effects of 3 different ARSIs in vitro and, in combination with enzalutamide, restricted proliferation of prostate cancer cells in vivo and in PDEs. CONCLUSION: Co-targeting HMMR and AR represents an effective strategy for improving response to ARSIs.
dc.description.statementofresponsibilityJosephine A. Hinneh, Joanna L. Gillis, Chui Yan Mah, Swati Irani, Raj K. Shrestha, Natalie K. Ryan, Enomoto Atsushi, Zeyad D. Nassar, David J. Lynn, Luke A. Selth, Masashi Kato, Margaret M. Centenera and Lisa M. Butler
dc.identifier.citationBritish Journal of Cancer, 2023; 129(8):1350-1361
dc.identifier.doi10.1038/s41416-023-02406-8
dc.identifier.issn0007-0920
dc.identifier.issn1532-1827
dc.identifier.orcidHinneh, J.A. [0000-0003-0207-8453]
dc.identifier.orcidMah, C.Y. [0000-0002-8820-4037]
dc.identifier.orcidNassar, Z.D. [0000-0002-7779-2697]
dc.identifier.orcidSelth, L.A. [0000-0002-4686-1418]
dc.identifier.orcidCentenera, M.M. [0000-0002-2206-0632]
dc.identifier.orcidButler, L.M. [0000-0003-2698-3220]
dc.identifier.urihttps://hdl.handle.net/2440/140014
dc.language.isoen
dc.publisherSpringer Nature
dc.rights© The Author(s) 2023. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
dc.source.urihttps://doi.org/10.1038/s41416-023-02406-8
dc.subjectCastration-Resistant
dc.subject.meshCell Line, Tumor
dc.subject.meshAnimals
dc.subject.meshHumans
dc.subject.meshMice
dc.subject.meshProstatic Neoplasms
dc.subject.meshNitriles
dc.subject.meshReceptors, Androgen
dc.subject.meshRNA, Small Interfering
dc.subject.meshCell Proliferation
dc.subject.meshDrug Resistance, Neoplasm
dc.subject.meshMale
dc.subject.meshProstatic Neoplasms, Castration-Resistant
dc.titleTargeting hyaluronan-mediated motility receptor (HMMR) enhances response to androgen receptor signalling inhibitors in prostate cancer
dc.typeJournal article
pubs.publication-statusPublished

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