Targeting amino acid metabolism for cancer therapy

Lukey, Michael J.; Katt, William P.; Cerione, Richard A.

doi:10.1016/j.drudis.2016.12.003

Cited by 236 publications

(189 citation statements)

References 64 publications

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“…2,3 A Surveillance, Epidemiology, and End Results data analysis from 1975 to 2013 found that the 5-year relative survival rate of AA patients with BLCA was close to 66%, whereas European Americans (EAs) with BLCA had a survival rate close to 80%. 6 They also play a role in signal transduction, and their derivatives act as cofactors for many enzymes that play major roles in cancer progression. Emerging evidence suggests that both genetic and other biological factors play a role in racial disparities associated with BLCA; however, the poor survival of AA patients with BLCA is also due to late diagnoses and more aggressive tumor stages among AAs.…”

Section: Introductionmentioning

confidence: 99%

“…Amino acids contribute to the biosynthesis of nucleotides, proteins, and lipids and the replenishment of tricarboxylic acid (TCA) cycle intermediates. 6 They also play a role in signal transduction, and their derivatives act as cofactors for many enzymes that play major roles in cancer progression. Among them is lysine demethylase 2A (KDM2A), which is an α-ketoglutaric acid-dependent, Jumonji C-containing histone demethylase Cancer March 15, 2019 that plays a crucial role in tumor progression through the suppression of matrix metalloproteinases (2, 9, 14, and 15).…”

Section: Introductionmentioning

confidence: 99%

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Large‐scale profiling of serum metabolites in African American and European American patients with bladder cancer reveals metabolic pathways associated with patient survival

Vantaku

Donepudi

Piyarathna

et al. 2019

Cancer

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BACKGROUND: African Americans (AAs) experience a disproportionally high rate of bladder cancer (BLCA) deaths even though their incidence rates are lower than those of other patient groups. Using a metabolomics approach, this study investigated how AA BLCA may differ molecularly from European Americans (EAs) BLCA, and it examined serum samples from patients with BLCA with the aim of identifying druggable metabolic pathways in AA patients. METHODS: Targeted metabolomics was applied to measure more than 300 metabolites in serum samples from 2 independent cohorts of EA and AA patients with BLCA and healthy EA and AA controls via liquid chromatography-mass spectrometry, and this was followed by the identification of altered metabolic pathways with a focus on AA BLCA. A subset of the differential metabolites was validated via absolute quantification with the Biocrates AbsoluteIDQ p180 kit. The clinical significance of the findings was further examined in The Cancer Genomic Atlas BLCA data set. RESULTS: Fifty-three metabolites, mainly related to amino acid, lipid, and nucleotide metabolism, were identified that showed significant differences in abundance between AA and EA BLCA. For example, the levels of taurine, glutamine, glutamate, aspartate, and serine were elevated in serum samples from AA patients versus EA patients. By mapping these metabolites to genes, this study identified significant relations with regulators of metabolism such as malic enzyme 3, prolyl 3-hydroxylase 2, and lysine demethylase 2A that predicted patient survival exclusively in AA patients with BLCA. CONCLUSIONS: This metabolic profile of serum samples might be used to assess risk progression in AA BLCA. These first-in-field findings describe metabolic alterations in AA BLCA and emphasize a potential biological basis for BLCA health disparities. Cancer 2019;125:921-932.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Large‐scale profiling of serum metabolites in African American and European American patients with bladder cancer reveals metabolic pathways associated with patient survival

Vantaku

Donepudi

Piyarathna

et al. 2019

Cancer

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“…Recent advances in our knowledge of cancer metabolism suggest that targeting amino acid metabolism represents a promising strategy for the development of novel therapeutic agents (7). A traditional treatment that targets amino acids is L-asparaginase (ASNase).…”

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confidence: 99%

Inhibition of GCN2 sensitizes ASNS-low cancer cells to asparaginase by disrupting the amino acid response

Nakamura

Nambu

Ebara

et al. 2018

Proc. Natl. Acad. Sci. U.S.A.

119

122

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General control nonderepressible 2 (GCN2) plays a major role in the cellular response to amino acid limitation. Although maintenance of amino acid homeostasis is critical for tumor growth, the contribution of GCN2 to cancer cell survival and proliferation is poorly understood. In this study, we generated GCN2 inhibitors and demonstrated that inhibition of GCN2 sensitizes cancer cells with low basal-level expression of asparagine synthetase (ASNS) to the antileukemic agent l-asparaginase (ASNase) in vitro and in vivo. We first tested acute lymphoblastic leukemia (ALL) cells and showed that treatment with GCN2 inhibitors rendered ALL cells sensitive to ASNase by preventing the induction of ASNS, resulting in reduced levels of de novo protein synthesis. Comprehensive gene-expression profiling revealed that combined treatment with ASNase and GCN2 inhibitors induced the stress-activated MAPK pathway, thereby triggering apoptosis. By using cell-panel analyses, we also showed that acute myelogenous leukemia and pancreatic cancer cells were highly sensitive to the combined treatment. Notably, basal ASNS expression at protein levels was significantly correlated with sensitivity to combined treatment. These results provide mechanistic insights into the role of GCN2 in the amino acid response and a rationale for further investigation of GCN2 inhibitors for the treatment of cancer.

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“…As nutrients, amino acids are required for protein synthesis, growth, and invasiveness of tumor cells . However, integrative screening of transcriptional regulators of amino acid metabolic genes in NB remains unknown.…”

Section: Discussionmentioning

confidence: 99%

Therapeutic Targeting of MZF1‐AS1/PARP1/E2F1 Axis Inhibits Proline Synthesis and Neuroblastoma Progression

et al. 2019

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Proline synthesis plays an important role in the metabolic reprogramming that contributes to tumor progression. However, the mechanisms regulating expression of proline synthetic genes in neuroblastoma (NB) remain elusive. Herein, through integrative screening of a public dataset and amino acid profiling analysis, myeloid zinc finger 1 (MZF1) and MZF1 antisense RNA 1 (MZF1‐AS1) are identified as transcriptional regulators of proline synthesis and NB progression. Mechanistically, transcription factor MZF1 promotes the expression of aldehyde dehydrogenase 18 family member A1 and pyrroline‐5‐carboxylate reductase 1, while proline facilitates the aggressiveness of NB cells. In addition, MZF1‐AS1 binds poly(ADP‐ribose) polymerase 1 (PARP1) to facilitate its interaction with E2F transcription factor 1 (E2F1), resulting in transactivation of E2F1 and upregulation of MZF1 and other oncogenic genes associated with tumor progression. Administration of a small peptide blocking MZF1‐AS1‐PARP1 interaction or lentivirus‐mediated short hairpin RNA targeting MZF1‐AS1 suppresses the proline synthesis, tumorigenesis, and aggressiveness of NB cells. In clinical NB cases, high expression of MZF1‐AS1, PARP1, E2F1, or MZF1 is associated with poor survival of patients. These results indicate that therapeutic targeting of MZF1‐AS1/PARP1/E2F1 axis inhibits proline synthesis and NB progression.

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Targeting amino acid metabolism for cancer therapy

Cited by 236 publications

References 64 publications

Large‐scale profiling of serum metabolites in African American and European American patients with bladder cancer reveals metabolic pathways associated with patient survival

Large‐scale profiling of serum metabolites in African American and European American patients with bladder cancer reveals metabolic pathways associated with patient survival

Inhibition of GCN2 sensitizes ASNS-low cancer cells to asparaginase by disrupting the amino acid response

Therapeutic Targeting of MZF1‐AS1/PARP1/E2F1 Axis Inhibits Proline Synthesis and Neuroblastoma Progression

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