The Transsulfuration Pathway Makes, the Tumor Takes

Weber, Ross A.; Birsoy, Kıvanç

doi:10.1016/j.cmet.2019.10.009

Cited by 13 publications

(14 citation statements)

References 10 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Interestingly, increased expression of Cystathionine-β-synthase (CBS), an enzymatic component of transsulfuration pathway, was evident in cells with resistance to ferroptosis induced by Erastin, a common used inhibitor of xCT [8] . The transsulfuration pathway together with the methionine cycle, acts as an important source of endogenous cysteine, especially in the ablation of xCT mediated extracellular source of cysteine [9] . CBS has also been confirmed as an independent regulator of ferroptosis [ 10 , 11 ].…”

Section: Introductionmentioning

confidence: 99%

Endogenous hydrogen sulfide regulates xCT stability through persulfidation of OTUB1 at cysteine 91 in colon cancer cells

Chen

Zhu

et al. 2021

Neoplasia

View full text Add to dashboard Cite

Increased xCT and transsulfuration pathway has been associated with metabolic reprogramming of colorectal cancer. However, the correlation between these 2 events and the underlying molecular mechanism remains obscure. xCT expression was determined in tissue microarrays of colorectal cancer. RNA sequencing and functional assays in vitro was adopted to delineate the involvement of transsulfuration pathway in the proper function of xCT in maintaining the chemoresistant phenotype. The synthetic lethality of blocking xCT and the transsulfuration pathway was investigated both in vitro and in vivo . The up-regulation of the transsulfuration pathway after inhibiting xCT in colon cancer cells was evident and exogenous H 2 S partially reversed the loss of chemoresistance phenotype after inhibiting xCT. Mechanistically, CTH derived H 2 S increased the stability of xCT through persulfidation of OTU domain-containing ubiquitin aldehyde-binding protein 1 at cysteine 91. AOAA and Erastin resulted in synthetic lethality both in vitro and in vivo , which was mediated through increased ferroptosis and apoptosis. Our findings suggest that a reciprocal regulation exists between xCT and the transsulfuration pathway, which is a targetable metabolic vulnerability. Mechanistically, CTH derived H 2 S increased the stability of xCT through persulfidation of OTU domain-containing ubiquitin aldehyde-binding protein 1 at cysteine 91.

show abstract

Section: Introductionmentioning

confidence: 99%

Endogenous hydrogen sulfide regulates xCT stability through persulfidation of OTUB1 at cysteine 91 in colon cancer cells

Chen

Zhu

et al. 2021

Neoplasia

View full text Add to dashboard Cite

show abstract

“…Significances on Figs. 1 B , 4 B , and 5 D and H and SI Appendix , Fig. S1 D – F represent significant differences between basal and all other groups.…”

Section: Methodsmentioning

confidence: 94%

“…Measured values were compared using Student’s t test except for the proteomics data ( Figs. 1 B , 4 B , and 5 D and H ) in which differential expression analysis of quantitative mass spectrometry (DEqMS) was used ( 61 ). Significances on Figs.…”

Section: Methodsmentioning

confidence: 99%

“…Consequently, recognized vulnerabilities of cancer cells to particular metabolic pathways represent a major focus in current drug development endeavors ( 4 ). Recent studies ( 5 , 6 ) demonstrated that carcinogenic rewiring of the metabolism of the nonessential amino acid cysteine (Cys) can support cancer cell growth ( 6 ). Cys residues in proteins and in glutathione (GSH) are critical primary targets of reactive oxygen species (ROS) and play major roles in antioxidant protection and redox regulation of cellular signaling and metabolism ( 7 – 10 ).…”

mentioning

confidence: 99%

See 1 more Smart Citation

Reprogrammed transsulfuration promotes basal-like breast tumor progression via realigning cellular cysteine persulfidation

Erdélyi

Ditrói

Johansson

et al. 2021

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

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.

show abstract

“…Moreover, it has been involved in tumor growth. [18,43,44] Since diet can impact H 2 S production, [44] it still remains to be established which dietary requirements and nutrients are involved in the control of endogenous H 2 S production.…”

Section: Discussionmentioning

confidence: 99%

Maternal Fructose Intake Increases Liver H₂S Synthesis but Exarcebates its Fructose‐Induced Decrease in Female Progeny

Fauste

Rodrigo

Aguirre

et al. 2020

Molecular Nutrition Food Res

View full text Add to dashboard Cite

Scope Fructose intake from added sugars correlates with the epidemic rise in metabolic syndrome and cardiovascular diseases (CVD). However, consumption of beverages containing fructose is allowed during gestation. Homocysteine (Hcy) is a well‐known risk factor for CVD while hydrogen sulfide (H2S), a product of its metabolism, has been proved to exert opposite effects to Hcy. Methods and results First, it is investigated whether maternal fructose intake produces subsequent changes in Hcy metabolism and H2S synthesis of the progeny. Carbohydrates are supplied to pregnant rats in drinking water (10% wt/vol) throughout gestation. Adult female descendants from fructose‐fed, control or glucose‐fed mothers are studied. Females from fructose‐fed mothers have elevated homocysteinemia, hepatic H2S production, cystathionine γ‐lyase (CSE) (the key enzyme in H2S synthesis) expression and plasma H2S, versus the other two groups. Second, it is studied how adult female progeny from control (C/F), fructose‐ (F/F), and glucose‐fed (G/F) mothers responded to liquid fructose and compared them to the control group (C/C). Interestingly, hepatic CSE expression and H2S synthesis are diminished by fructose intake, this effect being more pronounced in F/F females. Conclusion Maternal fructose intake produces a fetal programming that increases hepatic H2S production and, in contrast, exacerbates its fructose‐induced drop in female progeny.

show abstract

The Transsulfuration Pathway Makes, the Tumor Takes

Cited by 13 publications

References 10 publications

Endogenous hydrogen sulfide regulates xCT stability through persulfidation of OTUB1 at cysteine 91 in colon cancer cells

Endogenous hydrogen sulfide regulates xCT stability through persulfidation of OTUB1 at cysteine 91 in colon cancer cells

Reprogrammed transsulfuration promotes basal-like breast tumor progression via realigning cellular cysteine persulfidation

Maternal Fructose Intake Increases Liver H₂S Synthesis but Exarcebates its Fructose‐Induced Decrease in Female Progeny

Contact Info

Product

Resources

About

The Transsulfuration Pathway Makes, the Tumor Takes

Cited by 13 publications

References 10 publications

Endogenous hydrogen sulfide regulates xCT stability through persulfidation of OTUB1 at cysteine 91 in colon cancer cells

Endogenous hydrogen sulfide regulates xCT stability through persulfidation of OTUB1 at cysteine 91 in colon cancer cells

Reprogrammed transsulfuration promotes basal-like breast tumor progression via realigning cellular cysteine persulfidation

Maternal Fructose Intake Increases Liver H2S Synthesis but Exarcebates its Fructose‐Induced Decrease in Female Progeny

Contact Info

Product

Resources

About

Maternal Fructose Intake Increases Liver H₂S Synthesis but Exarcebates its Fructose‐Induced Decrease in Female Progeny