Cysteine Aminotransferase (CAT): A Pivotal Sponsor in Metabolic Remodeling and an Ally of 3-Mercaptopyruvate Sulfurtransferase (MST) in Cancer

Hipólito, Ana; Nunes, Sónia; Vicente, João B.; Serpa, Jacinta

doi:10.3390/molecules25173984

Cited by 19 publications

(25 citation statements)

References 169 publications

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“…Since GSH levels were not increased, we hypothesized that hydrogen sulfide (H 2 S) generation might underlie the antioxidant properties of Propranolol. H 2 S, a product of cysteine degradation ( 46 , 47 ), is a powerful antioxidant ( 48 ) with a reduction potential similar to the couple glutathione disulfide/glutathione (GSSG/GSH) ( 49 ). There was an increase in H 2 S production upon Propranolol administration, while Erastin did not affect H 2 S levels ( Figure 1J ).…”

Section: Resultsmentioning

confidence: 99%

The Activation of Endothelial Cells Relies on a Ferroptosis-Like Mechanism: Novel Perspectives in Management of Angiogenesis and Cancer Therapy

et al. 2021

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The activation of endothelial cells (ECs) is a crucial step on the road map of tumor angiogenesis and expanding evidence indicates that a pro-oxidant tumor microenvironment, conditioned by cancer metabolic rewiring, is a relevant controller of this process. Herein, we investigated the contribution of oxidative stress-induced ferroptosis to ECs activation. Moreover, we also addressed the anti-angiogenic effect of Propranolol. We observed that a ferroptosis-like mechanism, induced by xCT inhibition with Erastin, at a non-lethal level, promoted features of ECs activation, such as proliferation, migration and vessel-like structures formation, concomitantly with the depletion of reduced glutathione (GSH) and increased levels of oxidative stress and lipid peroxides. Additionally, this ferroptosis-like mechanism promoted vascular endothelial cadherin (VE-cadherin) junctional gaps and potentiated cancer cell adhesion to ECs and transendothelial migration. Propranolol was able to revert Erastin-dependent activation of ECs and increased levels of hydrogen sulfide (H2S) underlie the mechanism of action of Propranolol. Furthermore, we tested a dual-effect therapy by promoting ECs stability with Propranolol and boosting oxidative stress to induce cancer cell death with a nanoformulation comprising selenium-containing chrysin (SeChry) encapsulated in a fourth generation polyurea dendrimer (SeChry@PUREG4). Our data showed that novel developments in cancer treatment may rely on multi-targeting strategies focusing on nanoformulations for a safer induction of cancer cell death, taking advantage of tumor vasculature stabilization.

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Section: Resultsmentioning

confidence: 99%

The Activation of Endothelial Cells Relies on a Ferroptosis-Like Mechanism: Novel Perspectives in Management of Angiogenesis and Cancer Therapy

et al. 2021

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“…3-Mercaptopyruvate is produced from cysteine by cysteine aminotransferase (CAT; EC 2.6.1.3). Cooperation of MPST: CAT enzymatic system allows for transferring the sulfur from cysteine to active site cysteine and further to acceptor protein [ 164 ]. The transfer of sulfane sulfur is one of the possible mechanisms of persulfide species (Cys-SSH, GSSH, protein-SSH) formation [ 146 ].…”

Section: Sulfurtransferasesmentioning

confidence: 99%

Sulfur Administration in Fe–S Cluster Homeostasis

2021

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Mitochondria are the key organelles of Fe–S cluster synthesis. They contain the enzyme cysteine desulfurase, a scaffold protein, iron and electron donors, and specific chaperons all required for the formation of Fe–S clusters. The newly formed cluster can be utilized by mitochondrial Fe–S protein synthesis or undergo further transformation. Mitochondrial Fe–S cluster biogenesis components are required in the cytosolic iron–sulfur cluster assembly machinery for cytosolic and nuclear cluster supplies. Clusters that are the key components of Fe–S proteins are vulnerable and prone to degradation whenever exposed to oxidative stress. However, once degraded, the Fe–S cluster can be resynthesized or repaired. It has been proposed that sulfurtransferases, rhodanese, and 3-mercaptopyruvate sulfurtransferase, responsible for sulfur transfer from donor to nucleophilic acceptor, are involved in the Fe–S cluster formation, maturation, or reconstitution. In the present paper, we attempt to sum up our knowledge on the involvement of sulfurtransferases not only in sulfur administration but also in the Fe–S cluster formation in mammals and yeasts, and on reconstitution-damaged cluster or restoration of enzyme’s attenuated activity.

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“…However, given the pro-metastatic roles of STAT3 (145)(146)(147)(148)(149), GOT-2 may be related to the prometastatic effects of STAT3. Moreover, GOT-1 and -2 also display a cysteine aminotransferase (CAT) activity, catalyzing the transamination of cysteine to 3-mercaptopyruvate and glutamate (143). Cysteine is an amino acid, which has three main associated catabolic routes: the cystathionine-b-synthase (CBS); the cystathionine-g-lyase (CSE) and the CAT/GOT:3mercaptopyruvate sulfurtransferase (MST) axis; all of them producing H 2 S concomitantly with cysteine degradation.…”

Section: Amino Acid Metabolismmentioning

confidence: 99%

“…STAT3 regulates EMT, cell migration and invasion, and is also indirectly related to hypoxia-related cancer metabolic remodeling, under the control of HIF-1α ( 142 ). Moreover, glutamate is also a substrate for glutamic-oxaloacetic transaminase 1 and 2 (GOT-1 and -2), resulting α-KG and aspartate, at the expense of oxaloacetate ( 143 ). GOT-2 is directly regulated by STAT3 in lymphoma ( 144 ), but few studies have focused on the role of any form of GOT in metastasis.…”

Section: Rewired Metabolic Traits In Metastasis a Way Of Surviving Outside Of The Primary Tumormentioning

confidence: 99%

Molecular and Metabolic Reprogramming: Pulling the Strings Toward Tumor Metastasis

et al. 2021

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Metastasis is a major hurdle to the efficient treatment of cancer, accounting for the great majority of cancer-related deaths. Although several studies have disclosed the detailed mechanisms underlying primary tumor formation, the emergence of metastatic disease remains poorly understood. This multistep process encompasses the dissemination of cancer cells to distant organs, followed by their adaptation to foreign microenvironments and establishment in secondary tumors. During the last decades, it was discovered that these events may be favored by particular metabolic patterns, which are dependent on reprogrammed signaling pathways in cancer cells while they acquire metastatic traits. In this review, we present current knowledge of molecular mechanisms that coordinate the crosstalk between metastatic signaling and cellular metabolism. The recent findings involving the contribution of crucial metabolic pathways involved in the bioenergetics and biosynthesis control in metastatic cells are summarized. Finally, we highlight new promising metabolism-based therapeutic strategies as a putative way of impairing metastasis.

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Cysteine Aminotransferase (CAT): A Pivotal Sponsor in Metabolic Remodeling and an Ally of 3-Mercaptopyruvate Sulfurtransferase (MST) in Cancer

Cited by 19 publications

References 169 publications

The Activation of Endothelial Cells Relies on a Ferroptosis-Like Mechanism: Novel Perspectives in Management of Angiogenesis and Cancer Therapy

The Activation of Endothelial Cells Relies on a Ferroptosis-Like Mechanism: Novel Perspectives in Management of Angiogenesis and Cancer Therapy

Sulfur Administration in Fe–S Cluster Homeostasis

Molecular and Metabolic Reprogramming: Pulling the Strings Toward Tumor Metastasis

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