Is Development of High-Grade Gliomas Sulfur-Dependent?

Abstract

Abstract:We characterized γ-cystathionase, rhodanese and 3-mercaptopyruvate sulfurtransferase activities in various regions of human brain (the cortex, thalamus, hypothalamus, hippocampus, cerebellum and subcortical nuclei) and human gliomas with II to IV grade of malignancy (according to the WHO classification). The human brain regions, as compared to human liver, showed low γ-cystathionase activity. The activity of rhodanese was also much lower and it did not vary significantly between the investigated brain regions. The activity of 3-mercaptopyruvate sulfurtransferase was the highest in the thalamus, hypothalamus and subcortical nuclei and essentially the same level of sulfane sulfur was found in all the investigated brain regions. The investigations demonstrated that the level of sulfane sulfur in gliomas with the highest grades was high in comparison to various human brain regions, and was correlated with a decreased activity of γ-cystathionase, 3-mercaptopyruvate sulfurtransferase and rhodanese. This can suggest sulfane sulfur accumulation and points to its importance for malignant cell proliferation and tumor growth. In gliomas with the highest grades of malignancy, despite decreased levels of total free cysteine and total free glutathione, a high ratio of GSH/GSSG was maintained, which is important for the process of malignant cells proliferation. A high level of sulfane sulfur and high GSH/GSSG ratio could result in the elevated hydrogen sulfide levels. Because of the OPEN ACCESSMolecules 2014, 19 21351 disappearance of γ-cystathionase activity in high-grade gliomas, it seems to be possible that 3-mercaptopyruvate sulfurtransferase could participate in hydrogen sulfide production. The results confirm sulfur dependence of malignant brain tumors.

In vivo 1H MRS detection of cystathionine in human brain tumors

“…We have recently shown that higher cystathionine levels are associated with 1p/19q codeletion and that cystathionine could represent a noninvasive marker of abnormal expression of cystathionine‐pathway genes such as cystathionine gamma‐lyase and cystathionine beta‐synthase . In a previous ex vivo study, the changed profile of cystathionine gamma‐lyase activity and cystathionine levels in gliomas were correlated, and both of them decreased with the increase of the grade of glioma malignancy . Additionally, our observations suggested that cystathionine increase is associated with enhanced cystathionine beta‐synthase activity likely due to a compensatory mechanism induced by oxidative stress, and that this process may be exacerbated in the presence of 1p/19q codeletion due to reduced activity of cystathionine gamma‐lyase (located on chromosome 1p) .…”

“…Higher cystathionine levels in brain tumors compared to normal tissue were reported previously from ex vivo tissue analysis . In particular, tumors of glial origin showed the highest cystathionine concentrations, suggesting that cystathionine is preferentially synthesized in glial cells .…”

“…In particular, tumors of glial origin showed the highest cystathionine concentrations, suggesting that cystathionine is preferentially synthesized in glial cells . In general, the average cystathionine level in higher grade gliomas (II/III, III/IV, IV) was higher relative to low‐grade gliomas (II), with no genetic information provided . Abnormal accumulation of cystathionine in breast cancer was also reported, and cystathionine was suggested to be a novel oncometabolite possibly contributing to drug resistance in cancer cells.…”

“…5,12 Higher cystathionine levels in brain tumors compared to normal tissue were reported previously from ex vivo tissue analysis. 6,13 In particular, tumors of glial origin showed the highest cystathionine concentrations, suggesting that cystathionine is preferentially synthesized in glial cells. 6 In general, the average cystathionine level in higher grade gliomas (II/III, III/IV, IV) was higher relative to low-grade gliomas (II), with no genetic information provided.…”

Signalling by hydrogen sulfide and polysulfides via protein S‐sulfuration

“…Further studies are awaited to clarify the mechanisms of responses to H 2 S that are conflicting depending on the type of cancer. Wrobel et al (2014) reported that the levels of sulfane sulfur (polysulfides) in gliomas with the highest grades of malignancy are greater than those of glioma-free brain regions. A similar result was also reported in glioblastoma-bearing ipsilateral hemispheres, which contain greater amounts of H 2 S n than the glioblastoma-free control hemispheres (Shiota et al, 2018).…”