Proline Metabolism in Malignant Gliomas: A Systematic Literature Review

Abstract

Background: Proline has attracted growing interest because of its diverse influence on tumor metabolism and the discovery of the regulatory mechanisms that appear to be involved. In contrast to general oncology, data on proline metabolism in central nervous system malignancies are limited. Materials and Methods: We performed a systematic literature review of the MEDLINE and EMBASE databases according to PRISMA guidelines, searching for articles concerning proline metabolism in malignant glial tumors. From 815 search results, we identified 14 studies pertaining to this topic. Results: The role of the proline cycle in maintaining redox balance in IDH-mutated gliomas has been convincingly demonstrated. Proline is involved in restoring levels of glutamate, the main glial excitatory neurotransmitter. Proline oxidase influences two major signaling pathways: p53 and NF- κB. In metabolomics studies, the metabolism of proline and its link to the urea cycle was found to be a prognostic factor for survival and a marker of malignancy. Data on the prolidase concentration in the serum of glioblastoma patients are contradictory. Conclusions: Despite a paucity of studies in the literature, the available data are interesting enough to encourage further research, especially in terms of extrapolating what we have learned of proline functions from other neoplasms to malignant gliomas.

Transcriptome Analysis of Redox Systems and Polyamine Metabolic Pathway in Hepatoma and Non-Tumor Hepatocyte-like Cells

“…Next, we assessed the mRNA levels of enzymes of the urea cycle and proline metabolism, since the polyamine precursor putrescine is synthesized from a non-proteinogenic amino acid ornithine of this cycle, which is also linked to Pro/Glu metabolic system [ 12 , 52 ]. The results, presented in Figure 5 a–c, show that in hepatocyte-like HepaRG cells, the level of the transcript encoding argininosuccinate synthase (ASS1) is fifteen-fold higher than in Huh7.5 cells, and the mRNA of the argininosuccinate lyase gene (ASL), which synthesizes arginine, is two times higher.…”

“…In Huh7.5 hepatoma cells, the expression of proteins synthesizing proline from P5C (PYCR1, PYCR2, PYCR3) prevails over proline-utilizing proteins (PRODH and PRODH2) and the coordinated action of PYCR3, PRODH, and PRODH2 proteins. P5C, being exported into the cytoplasm, is converted into proline, resulting in proline being transferred back to the mitochondria, where it was again oxidized into P5C by PRODH and PRODH2 [ 52 ]. Hence, a closed cycle leads to an increase in the concentration of NADP + in the cytoplasm and the generation of ROS in mitochondria [ 73 ].…”

UHPLC-HRMS-based metabolomic and lipidomic characterization of glioma cells in response to anlotinib

“…Current literatures found that the concentration of proline in GBM was higher than in normal brain 32 . Similarly, IDH-mutant high-grade oligodendrogliomas was found to utilize the proline cycle as a redox shuttle to maintain redox balance 33 . Our findings support the hypothesis that regulating the disorder of arginine and proline metabolism pathway in cancer cells can affect the proliferation of tumor cells, which provides a new idea for the targeted therapy of glioma.…”

Metabolomics in High Grade Gliomas

“…Proline is oxidized to glutamate in the mitochondria and has been linked to glutamate metabolism in GBM and cell proliferation (Cappelletti et al, 2018). In a recent systematic review, Sawicka et al found proline to be a prognostic factor and a signal of malignancy (Sawicka et al, 2022).…”