Reprogrammed transsulfuration promotes basal-like breast tumor progression via realigning cellular cysteine persulfidation.
Reprogrammed transsulfuration promotes basal-like breast tumor progression via realigning cellular cysteine persulfidation.
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重编程转硫通过重组细胞半胱氨酸过硫化促进基底样乳腺肿瘤的进展。
DOI：
10.1073/pnas.2100050118
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发表时间：
2021-11-09
影响因子：
11.1
通讯作者：
Nagy P
中科院分区：
文献类型：
--
作者：
Erdélyi K;Ditrói T;Johansson HJ;Czikora Á;Balog N;Silwal-Pandit L;Ida T;Olasz J;Hajdú D;Mátrai Z;Csuka O;Uchida K;Tóvári J;Engebraten O;Akaike T;Børresen Dale AL;Kásler M;Lehtiö J;Nagy P
基底样乳腺癌（BLBC）预后不良。在此，我们提供证据表明重编程的转硫作用是BLBC的一个特征。人类BLBC肿瘤表现出胱硫醚β - 合成酶（CBS）水平升高，但氧化型半胱氨酸分解代谢酶表达降低，呈现出一种对半胱氨酸成瘾的表型。我们证明在BLBC细胞中，CBS在细胞增殖和侵袭性、缺氧条件下HIF1 - α的激活以及对氧化应激和胱氨酸（CySSCy）剥夺诱导的铁死亡的保护中起作用。在shCBS异种移植肿瘤中，肿瘤进展和血管生成受损，肿瘤内坏死区域更大。基于硫代谢组和蛋白质组学数据的机制分析表明，重新调整的半胱氨酸过硫化是BLBC肿瘤这种对半胱氨酸成瘾表型的一个决定性因素，这为药物开发带来了希望。
基底样乳腺癌（BLBC）是乳腺肿瘤中最具侵袭性的亚型，预后不良且分子靶向治疗选择有限。我们表明BLBC细胞对半胱氨酸有高需求且半胱氨酸代谢重编程。来自四个不同队列的患者来源的BLBC肿瘤表现出转硫酶胱硫醚β - 合成酶（CBS）表达升高。CBS沉默（shCBS）使BLBC细胞侵袭性降低、增殖减慢、更易受氧化应激和胱氨酸（CySSCy）剥夺的影响、易发生铁死亡，并且在缺氧条件下对HIF1 - α激活的反应性降低。shCBS异种移植肿瘤比对照组生长更慢，并且血管生成受损，坏死区域更大。硫代谢物分析表明，CBS重新调整的硫化物/过硫化物诱导功能在BLBC肿瘤进展中很重要。支持这一点的是，排除丝氨酸（CBS用于产生半胱氨酸但不用于产生硫化物/过硫化物的底物）并没有加剧shCBS BLBC细胞中胱氨酸（CySSCy）剥夺诱导的铁死亡。在shCBS细胞和异种移植中检测到酪氨酸磷酸化受损，可能是由于过硫化抑制了磷酸酶功能。胱硫醚γ - 裂解酶（CSE）的过表达（它也有助于细胞内硫化物/过硫化物的产生）补偿了CBS活性的丧失，并且用CSE抑制剂处理shCBS异种移植进一步阻断了肿瘤生长。谷胱甘肽和蛋白质 - 半胱氨酸水平在shCBS细胞或异种移植中没有降低，但半胱氨酸过硫化水平和过硫化物分解代谢酶ETHE1的水平受到抑制。最后，氧化型半胱氨酸分解代谢途径的酶表达降低，但在人类BLBC肿瘤中产生过硫化物的CARS2表达升高。因此，产生过硫化物的途径是BLBC病理的主要可靶向决定因素，可用于治疗。
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.
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DOI：
10.1186/s13058-017-0812-y
发表时间：
2017-03-29
期刊：
Breast cancer research : BCR
影响因子：
--
作者：
Aure MR;Vitelli V;Jernström S;Kumar S;Krohn M;Due EU;Haukaas TH;Leivonen SK;Vollan HK;Lüders T;Rødland E;Vaske CJ;Zhao W;Møller EK;Nord S;Giskeødegård GF;Bathen TF;Caldas C;Tramm T;Alsner J;Overgaard J;Geisler J;Bukholm IR;Naume B;Schlichting E;Sauer T;Mills GB;Kåresen R;Mælandsmo GM;Lingjærde OC;Frigessi A;Kristensen VN;Børresen-Dale AL;Sahlberg KK;OSBREAC
通讯作者：
OSBREAC
影响因子：
82.9
作者：
通讯作者：
--
影响因子：
11.4
作者：
Mellis AT;Misko AL;Arjune S;Liang Y;Erdélyi K;Ditrói T;Kaczmarek AT;Nagy P;Schwarz G
通讯作者：
Schwarz G
DOI：
10.1083/jcb.201102095
发表时间：
2011-07-11
期刊：
The Journal of cell biology
影响因子：
--
作者：
Finkel T
通讯作者：
Finkel T
影响因子：
1.2
作者：
Borowicz, Stanley;Van Scoyk, Michelle;Winn, Robert A.
通讯作者：
Winn, Robert A.