TY - JOUR
T1 - Reprogrammed transsulfuration promotes basal-like breast tumor progression via realigning cellular cysteine persulfidation
AU - Erdelyi, Katalin
AU - Ditroi, Tamas
AU - Johansson, Henrik J.
AU - Czikora, Agnes
AU - Balog, Noemi
AU - Silwal-Pandit, Laxmi
AU - Ida, Tomoaki
AU - Olasz, Judit
AU - Hajdu, Dorottya
AU - Matrai, Zoltan
AU - Csuka, Orsolya
AU - Uchida, Koji
AU - Tovari, Jozsef
AU - Engebraten, Olav
AU - Akaike, Takaaki
AU - Børresen Dale, Anne Lise
AU - Kasler, Miklos
AU - Lehtio, Janne
AU - Nagy, Peter
N1 - Funding Information:
ACKNOWLEDGMENTS. This work was supported by the 2019 Hungarian Thematic Excellence Program TUDFO/51757/2019-ITM, TKP2020-NKA-26, the National Laboratories Excellence Program (under the National Tumorbiology Laboratory Project), and KH_126766, K_129286 from the Hungarian National Research, Development and Innovation Office. P.N. acknowledges the Japan Society for the Promotion of Science (Invitational Fellowship L19520). M.K., O.C., and P.N. acknowledge financial support from the NVKP_16-1-2016-0005 from the Hungarian National Research, Development and Innovation Office. J.L. is supported by financing from the European Union’s Horizon 2020 Research and Innovation Programme for the RESCUER project under Grant Agreement No. 847912, the Swedish Research Council, the Swedish Cancer Society, the Swedish Foundation for Strategic Research, and the Stockholm County Council; J.L. and H.J.J. are supported by the Cancer Society in Stockholm. The excellent technical assistance by Anna Mária Tóth and Anita Hidvégi and the valuable intellectual input and proofreading of the manuscript by Ed Schmidt are greatly appreciated.
Publisher Copyright:
© 2021 National Academy of Sciences. All rights reserved.
PY - 2021/11/9
Y1 - 2021/11/9
N2 - 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 persulfideproducing CARS2 was elevated in human BLBC tumors. Hence, the persulfide-producing pathways are major targetable determinants of BLBC pathology that could be therapeutically exploited.
AB - 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 persulfideproducing CARS2 was elevated in human BLBC tumors. Hence, the persulfide-producing pathways are major targetable determinants of BLBC pathology that could be therapeutically exploited.
KW - Basal-like breast cancer
KW - Cystathione β-synthetase
KW - Hydrogen sulfide
KW - Persulfide
KW - Transsulfuration
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U2 - 10.1073/pnas.2100050118
DO - 10.1073/pnas.2100050118
M3 - Article
C2 - 34737229
AN - SCOPUS:85119274860
VL - 118
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
SN - 0027-8424
IS - 45
M1 - e2100050118
ER -