Reprogrammed transsulfuration promotes basal-like breast tumor progression via realigning cellular cysteine persulfidation
| Autor: | Anne-Lise Børresen Dale, Tamás Ditrói, Ágnes Czikora, Katalin Erdelyi, Henrik J. Johansson, Tomoaki Ida, Koji Uchida, Judit Olasz, Laxmi Silwal-Pandit, Takaaki Akaike, Zoltán Mátrai, Miklós Kásler, József Tóvári, Olav Engebråten, Orsolya Csuka, Janne Lehtiö, Dorottya Hajdú, Noémi Balog, Péter Nagy |
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| Rok vydání: | 2021 |
| Předmět: |
persulfide
transsulfuration Angiogenesis hydrogen sulfide Cystathionine beta-Synthase Triple Negative Breast Neoplasms Transsulfuration Mice SCID Sulfides Cohort Studies cystathione β-synthetase chemistry.chemical_compound Animals Ferroptosis Humans Gene silencing Cysteine Pharmacology Multidisciplinary Neovascularization Pathologic Catabolism Glutathione Biological Sciences Oxidative Stress chemistry Tumor progression Disease Progression Cancer research Phosphorylation Female ETHE1 basal-like breast cancer |
| Zdroj: | Proceedings of the National Academy of Sciences of the United States of America |
| ISSN: | 1091-6490 0027-8424 |
| Popis: | Significance Basal-like breast cancers (BLBC) have poor prognosis. Here, we present evidence that reprogrammed transsulfuration is a hallmark of BLBC. Human BLBC tumors exhibit elevated levels of cystathione β-synthetase (CBS) but diminished expressions of oxidative Cys-catabolizing enzymes supporting a Cys-addicted phenotype. We demonstrated that in BLBC cells, CBS plays a role in cellular proliferation and invasiveness, HIF1-α activation under hypoxia, and protection against oxidative stress and CySSCy deprivation–induced ferroptosis. Tumor progression and angiogenesis was impaired in shCBS xenograft tumors, which had larger intratumoral necrotic areas. Mechanistic analyses largely based on sulfur metabolome and proteomics data revealed that realigned Cys persulfidation is a determining factor in this Cys-addicted phenotype of BLBC tumors, which holds promise for drug development. 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. |
| Databáze: | OpenAIRE |
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