Decreased Expression of Cystathionine β-Synthase Promotes Glioma Tumorigenesis

Abstract

Cystathionine β-synthase (CBS) catalyzes metabolic reactions that convert homocysteine to cystathionine. To assess the role of CBS in human glioma, cells were stably transfected with lentiviral vectors encoding short hairpin RNA (shRNA) targeting CBS or a non-targeting control shRNA and subclones were injected into immunodeficient mice. Interestingly, decreased CBS expression did not affect proliferation in vitro but decreased the latency period prior to rapid tumor xenograft growth after subcutaneous injection and increased tumor incidence and volume following orthotopic implantation into the caudate-putamen. In soft agar colony formation assays, CBS knockdown subclones displayed increased anchorage-independent growth. Molecular analysis revealed that CBS knockdown subclones expressed higher basal levels of the transcriptional activator hypoxia-inducible factor 2α (HIF-2α/EPAS1). HIF-2α knockdown counteracted the effect of CBS knockdown on anchorage-independent growth. Bioinformatic analysis of mRNA expression data from human glioma specimens revealed a significant association between low expression of CBS mRNA and high expression of angiopoietin-like 4 (ANGPTL4) and vascular endothelial growth factor (VEGF) transcripts, which are HIF-2 target gene products that were also increased in CBS knockdown subclones. These results suggest that decreased CBS expression in glioma increases HIF-2α protein levels and HIF-2 target gene expression, which promotes glioma tumor formation. Implications CBS loss of function promotes glioma growth.

Gasotransmitters in cancer: from pathophysiology to experimental therapy

“…1B). It must be pointed out, nevertheless, that in a glioma model, CBS silencing increased, rather than decreased tumour growth, 148 illustrating the different tumour-cell-type dependent roles of H 2 S. Notably, because CBS activity affects the cellular levels of cysteine and homocysteine and modulates oxidative status, the biological effects of CBS inhibition or silencing cannot be simply equated to the pharmacological inhibition of H 2 S production. 149 Moreover, the pharmacological effects of the most commonly used CBS inhibitor, AOAA, go well beyond CBS inhibition.…”

“…Indeed, there are several reports of: increased circulating and exhaled NO levels in patients with cancer; 182,183 increased carboxyhaemoglobin levels in colon cancers; 184 and increased exhaled H 2 S levels in patients with cancer (reviewed in 148 ).…”

Hydrogen Sulfide and Cancer

“…When subcutaneously or orthotopically injected into the flank of SCID mice, the subclone with CSE silencing exhibited a shorter latency period for tumor growth, as well as a more pronounced overall tumor growth rate. In addition to greater tumor volume, the CBS silenced tumors exhibited increased depth of invasion, vascular density, cell proliferation, and more apoptosis (Takano et al 2014). These findings unveil a role of CBS in glioma that is markedly different from its role in colon cancer or ovarian cancer.…”

“…These findings unveil a role of CBS in glioma that is markedly different from its role in colon cancer or ovarian cancer. As far as the mechanisms responsible for the observed effects, in vitro studies by Takano and colleagues showed that glioma cells respond to CBS silencing with increased VEGF and ANGPTL4 levels, higher HIF2a expression and increased anchorage-independent cell growth (Takano et al 2014). …”

Arginine dependence of tumor cells: targeting a chink in cancer’s armor

“…Currently, there is a resurgence of interest in enzyme-mediated amino acid deprivation as a new therapeutic approach for cancer treatment. 6,7,21,22 For example, arginine depletion can inhibit tumor cell proliferation and induce cell death pathways. Here we endeavor to provide a basic understanding of the roles of arginine in normal and tumor cell with emphasis on current knowledge and developments in the application of enzyme-mediated arginine-depriving therapy as a potential anti-cancer approach.…”