dc.date.accessioned | 2022-02-11T18:54:24Z | |
dc.date.available | 2022-02-11T18:54:24Z | |
dc.date.created | 2021-12-02T10:08:15Z | |
dc.date.issued | 2021 | |
dc.identifier.citation | Erdelyi, Katalin Ditroi, Tamas Johansson, Henrik J. Czikora, Agnes Balog, Noemi Silwal-Pandit, Laxmi Ida, Tomoaki Olasz, Judit Hajdu, Dorottya Matrai, Zoltan Csuka, Orsolya Uchida, Koji Tovari, Jozsef Engebråten, Olav Akaike, Takaaki Børresen Dale, Anne-Lise Kasler, Miklos Lehtio, Janne Nagy, Peter . Reprogrammed transsulfuration promotes basal-like breast tumor progression via realigning cellular cysteine persulfidation. Proceedings of the National Academy of Sciences of the United States of America. 2021, 118(45) | |
dc.identifier.uri | http://hdl.handle.net/10852/90815 | |
dc.description.abstract | Basal-like breast cancer (BLBC) is the most aggressive subtype of breast tumors with poor prognosis and limited molecular-targeted therapy options. We show that BLBC cells have a high Cys demand and reprogrammed Cys metabolism. Patient-derived BLBC tumors from four different cohorts exhibited elevated expression of the transsulfuration enzyme cystathione β-synthetase (CBS). CBS silencing (shCBS) made BLBC cells less invasive, proliferate slower, more vulnerable to oxidative stress and cystine (CySSCy) deprivation, prone to ferroptosis, and less responsive to HIF1-α activation under hypoxia. shCBS xenograft tumors grew slower than controls and exhibited impaired angiogenesis and larger necrotic areas. Sulfur metabolite profiling suggested that realigned sulfide/persulfide-inducing functions of CBS are important in BLBC tumor progression. Supporting this, the exclusion of serine, a substrate of CBS for producing Cys but not for producing sulfide/persulfide, did not exacerbate CySSCy deprivation–induced ferroptosis in shCBS BLBC cells. Impaired Tyr phosphorylation was detected in shCBS cells and xenografts, likely due to persulfidation-inhibited phosphatase functions. Overexpression of cystathione γ-lyase (CSE), which can also contribute to cellular sulfide/persulfide production, compensated for the loss of CBS activities, and treatment of shCBS xenografts with a CSE inhibitor further blocked tumor growth. Glutathione and protein-Cys levels were not diminished in shCBS cells or xenografts, but levels of Cys persulfidation and the persulfide-catabolizing enzyme ETHE1 were suppressed. Finally, expression of enzymes of the oxidizing Cys catabolism pathway was diminished, but expression of the persulfide-producing CARS2 was elevated in human BLBC tumors. Hence, the persulfide-producing pathways are major targetable determinants of BLBC pathology that could be therapeutically exploited. | |
dc.language | EN | |
dc.publisher | The National Academy of Sciences | |
dc.rights | Attribution-NonCommercial-NoDerivatives 4.0 International | |
dc.rights.uri | https://creativecommons.org/licenses/by-nc-nd/4.0/ | |
dc.title | Reprogrammed transsulfuration promotes basal-like breast tumor progression via realigning cellular cysteine persulfidation | |
dc.type | Journal article | |
dc.creator.author | Erdelyi, Katalin | |
dc.creator.author | Ditroi, Tamas | |
dc.creator.author | Johansson, Henrik J. | |
dc.creator.author | Czikora, Agnes | |
dc.creator.author | Balog, Noemi | |
dc.creator.author | Silwal-Pandit, Laxmi | |
dc.creator.author | Ida, Tomoaki | |
dc.creator.author | Olasz, Judit | |
dc.creator.author | Hajdu, Dorottya | |
dc.creator.author | Matrai, Zoltan | |
dc.creator.author | Csuka, Orsolya | |
dc.creator.author | Uchida, Koji | |
dc.creator.author | Tovari, Jozsef | |
dc.creator.author | Engebråten, Olav | |
dc.creator.author | Akaike, Takaaki | |
dc.creator.author | Børresen Dale, Anne-Lise | |
dc.creator.author | Kasler, Miklos | |
dc.creator.author | Lehtio, Janne | |
dc.creator.author | Nagy, Peter | |
cristin.unitcode | 185,53,49,12 | |
cristin.unitname | Institutt for kreftforskning | |
cristin.ispublished | true | |
cristin.fulltext | original | |
cristin.qualitycode | 2 | |
dc.identifier.cristin | 1963165 | |
dc.identifier.bibliographiccitation | info:ofi/fmt:kev:mtx:ctx&ctx_ver=Z39.88-2004&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.jtitle=Proceedings of the National Academy of Sciences of the United States of America&rft.volume=118&rft.spage=&rft.date=2021 | |
dc.identifier.jtitle | Proceedings of the National Academy of Sciences of the United States of America | |
dc.identifier.volume | 118 | |
dc.identifier.issue | 45 | |
dc.identifier.pagecount | 0 | |
dc.identifier.doi | https://doi.org/10.1073/pnas.2100050118 | |
dc.identifier.urn | URN:NBN:no-93424 | |
dc.type.document | Tidsskriftartikkel | |
dc.type.peerreviewed | Peer reviewed | |
dc.source.issn | 0027-8424 | |
dc.identifier.fulltext | Fulltext https://www.duo.uio.no/bitstream/handle/10852/90815/1/Reprogrammed%2Btranssulfuration%2Bpromotes%2Bbasal-like%2Bbreast%2Bcancer%2Bprogression%2Bvia%2Brealigning%2Bcellular%2Bcysteine%2Bpersulfidation.pdf | |
dc.type.version | PublishedVersion | |
cristin.articleid | e2100050118 | |