Microbial enzymes for deprivation of amino acid metabolism in malignant cells: biological strategy for cancer treatment

Gao

et al. 2020

Front. Mol. Neurosci.

Background : Parkinson’s disease (PD) is the second most common neurodegenerative disease worldwide and involves deficiencies in alpha-synuclein (α-Syn) degradation. Effective therapeutic strategies for PD are urgently needed. L-asparaginase (L-ASNase) has been developed for therapeutic applications in many fields because it catalyzes the hydrolysis of asparagine and glutamine in cancer cells, which may also activate autophagy and induce the degradation of accumulated α-Syn. However, the efficacy and related mechanism of L-ASNase in PD remain poorly understood. Methods : We determined the correlation between L-ASNase and autophagic degradation of α-Syn in a cell model of PD. Mitochondrial function and apoptosis were examined in the presence or absence of L-ASNase. Then, we applied GC-MS/MS targeted amino acid metabolomics analysis to validate the amino acid regulation induced by L-ASNase treatment. Glutamine was added to verify whether the neuroprotective effect was induced by deprivation of glutamine. α-Syn-related autophagy and mitochondrial fusion/fission dynamics were detected to explore the mechanism of L-ASNase-based therapy in PD. Results : L-ASNase activated the autophagic degradation of α-Syn in a cell model of PD without cytotoxicity at specific concentrations/times. Under these conditions, L-ASNase showed substantial neuroprotective effects, including improvements in mitochondrial function and decreased apoptosis. Through GC-MS/MS targeted analysis, glutamine metabolism was identified as the target of L-ASNase in PD treatment, and the neuroprotective effect of L-ASNase was reduced after glutamine supplementation. Conclusions : Our study demonstrated for the first time that L-ASNase had a neuroprotective effect on a cell model of PD through a moderate deprivation of glutamine, which induced autophagic activation and mitochondrial fusion. Therefore, we demonstrated that L-ASNase could be a promising and effective drug for PD treatment.

Section: Discussionmentioning

confidence: 97%

L-Asparaginase Exerts Neuroprotective Effects in an SH-SY5Y-A53T Model of Parkinson’s Disease by Regulating Glutamine Metabolism

Gao

et al. 2020

Front. Mol. Neurosci.

“…Among different approaches in interrupting amino acid metabolism in cancer cells, enzymatic depletion is the most promising strategy. This results in deprivation of these exogenously supplied nutrients, and thus inhibits tumour growth 24 . Deprivation of amino acids including asparagine, 25 arginine, 26 glutamine, 27 methionine 28,29 and phenylalanine 30 has been tested for cancer treatment in experimental models.…”

Section: Discussionmentioning

confidence: 99%

The biological process of lysine‐tRNA charging is therapeutically targetable in liver cancer

Noordam

et al. 2020

Liver International

“…The TME plays a significant role in this process [ 166 ]. Therapies to disrupt tumor metabolism are currently being tested in clinical trials or clinically approved [ 167 , 168 , 169 ]. However, these therapies inhibit shared metabolic pathways in NK cells, and also lead to reduced NKG2D ligand expression in tumor cells [ 170 , 171 ].…”

Section: Conclusion and Future Considerationsmentioning

confidence: 99%

Design and Implementation of NK Cell-Based Immunotherapy to Overcome the Solid Tumor Microenvironment

Navin

Lam

Parihar

2020

Cancers

Natural killer (NK) cells are innate immune effectors capable of broad cytotoxicity via germline-encoded receptors and can have conferred cytotoxic potential via the addition of chimeric antigen receptors. Combined with their reduced risk of graft-versus-host disease (GvHD) and cytokine release syndrome (CRS), NK cells are an attractive therapeutic platform. While significant progress has been made in treating hematological malignancies, challenges remain in using NK cell-based therapy to combat solid tumors due to their immunosuppressive tumor microenvironments (TMEs). The development of novel strategies enabling NK cells to resist the deleterious effects of the TME is critical to their therapeutic success against solid tumors. In this review, we discuss strategies that apply various genetic and non-genetic engineering approaches to enhance receptor-mediated NK cell cytotoxicity, improve NK cell resistance to TME effects, and enhance persistence in the TME. The successful design and application of these strategies will ultimately lead to more efficacious NK cell therapies to treat patients with solid tumors. This review outlines the mechanisms by which TME components suppress the anti-tumor activity of endogenous and adoptively transferred NK cells while also describing various approaches whose implementation in NK cells may lead to a more robust therapeutic platform against solid tumors.