4.7 Review

Argininosuccinate synthase 1, arginine deprivation therapy and cancer management

Related references

Note: Only part of the references are listed.
Article Biotechnology & Applied Microbiology

N(6)-adenosine-methyltransferase-14 promotes glioma tumorigenesis by repressing argininosuccinate synthase 1 expression in an m6A-dependent manner

You-Qing Miao et al.

Summary: Glioma is a major cause of tumor-related deaths worldwide, and this study explores the role and mechanism of argininosuccinate synthase 1 (ASS1) in glioma. The findings show that downregulation of ASS1 is observed in glioma specimens and cell lines. Functionally, ASS1 inhibits glioma cell proliferation, migration, invasion, and growth. Furthermore, it is found that ASS1 is a target of METTL14-mediated N-6-methyladenosine (m(6)A) modification and that METTL14-mediated ASS1 mRNA degradation depends on the YTHDF2-dependent pathway. The study suggests that ASS1 may be an important regulator in glioma and the METTL14/ASS1/YTHDF2 axis could serve as a therapeutic target for glioma.

BIOENGINEERED (2022)

Article Oncology

A Phase 1 study of ADI-PEG20 (pegargiminase) combined with cisplatin and pemetrexed in ASS1-negative metastatic uveal melanoma

Pui Ying Chan et al.

Summary: This study evaluated the safety and activity of arginine depletion combined with chemotherapy in metastatic uveal melanoma (UM) patients. The results showed that ADI-PemCis treatment was well-tolerated and had a modest disease stabilizing effect in metastatic UM patients.

PIGMENT CELL & MELANOMA RESEARCH (2022)

Article Oncology

Phase 1 trial of ADI-PEG20 plus cisplatin in patients with pretreated metastatic melanoma or other advanced solid malignancies

Shuyang Yao et al.

Summary: In this study, the combination of ADI-PEG20 and cisplatin showed acceptable safety and demonstrated antitumor activity against metastatic ASS1-deficient solid tumors. Some patients achieved partial tumor responses after treatment, and most patients showed persistent arginine depletion and citrulline escalation at weeks 24 and 8 post-treatment. Tumor responses were associated with anti-ADI-PEG20 antibody levels at weeks 8 and 16.

BRITISH JOURNAL OF CANCER (2021)

Review Oncology

Arginine deprivation as a strategy for cancer therapy: An insight into drug design and drug combination

Yu Zhang et al.

Summary: Extensive studies have shown the importance of amino acid deprivation in cancer therapy, with arginine playing a pivotal role as a key nutrient for cancer cells. Arginine deiminase and human arginase are major protein drugs used for arginine deprivation, but they face common issues in clinical applications.

CANCER LETTERS (2021)

Article Oncology

A phase II clinical study on the efficacy and predictive biomarker of pegylated recombinant arginase on hepatocellular carcinoma

Stephen L. Chan et al.

Summary: The study aimed to evaluate the potential clinical efficacy of PEG-BCT-100 in chemo naive sorafenib-failure HCC patients. The results showed that the drug was well tolerated, and patients with ASS-negative tumors had a longer overall survival.

INVESTIGATIONAL NEW DRUGS (2021)

Article Oncology

Argininosuccinate synthase 1 suppresses tumor progression through activation of PERK/eIF2α/ATF4/CHOP axis in hepatocellular carcinoma

Sanghwa Kim et al.

Summary: The expression of ASS1 was higher in HCC spheroids than in monolayer cells, and high levels of ASS1 were associated with favorable overall survival in Korean HCC patients. Bidirectional interactions between ASS1 ER stress responses in HCC-derived spheroids limit HCC progression. Overexpression of ASS1 inhibited tumor growth and enhanced the efficacy of anti-HCC chemotherapy via activation of the PERK/eIF2 alpha/ATF4/CHOP axis, independent of p53 and arginine metabolism.

JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH (2021)

Article Oncology

ASS1 and ASL suppress growth in clear cell renal cell carcinoma via altered nitrogen metabolism

Sanika Khare et al.

Summary: By utilizing computational, genetic, and metabolomic tools along with in vivo animal models, this study elucidates the tumor-suppressive role of urea cycle enzymes ASS1 and ASL in ccRCC. The downregulation of ASS1 and ASL in ccRCC tumors leads to redirection of aspartate towards pyrimidine synthesis and enhanced proliferation, while also potentially regulating nitric oxide generation. This work enhances understanding of urea cycle enzymes in ccRCC progression and uncovers potential metabolic vulnerabilities in ccRCC.

CANCER & METABOLISM (2021)

Article Multidisciplinary Sciences

Naturally-occurring spinosyn A and its derivatives function as argininosuccinate synthase activator and tumor inhibitor

Zizheng Zou et al.

Summary: ASS1 acts as a tumor suppressor in breast cancer, and SPA and LM-2I can suppress breast tumor cell proliferation and growth by activating ASS1. Treatment with SPA and LM-2I significantly enhances ASS1 enzymatic activity in breast cancer cells, especially those with low ASS1 expression, leading to reduced pyrimidine synthesis and inhibition of cancer cell proliferation.

NATURE COMMUNICATIONS (2021)

Article Biochemistry & Molecular Biology

Snail enhances arginine synthesis by inhibiting ubiquitination-mediated degradation of ASS1

Hao Jia et al.

Summary: The study reveals that Snail promotes colorectal cancer migration by stabilizing argininosuccinate synthase 1 through preventing the degradation mediated by non-coding RNA LOC113230. Conversely, overexpression of LOC113230 suppresses CRC cell growth, migration, and lung metastasis. The findings suggest that TGF-beta and Snail promote arginine synthesis by inhibiting the LOC113230-mediated LRPPRC/TRAF2/ASS1 complex assembly, providing a potential target for new therapeutic approaches to treat CRC.

EMBO REPORTS (2021)

Review Biochemistry & Molecular Biology

Pyrimidine Biosynthetic Enzyme CAD: Its Function, Regulation, and Diagnostic Potential

Guanya Li et al.

Summary: CAD is a multifunctional protein involved in the initial steps of pyrimidine nucleotide synthesis, playing a central role in the synthesis of nucleic acids, active intermediates, and cell membranes. Deregulation of CAD-related pathways or CAD mutations can lead to various diseases such as cancer, neurological disorders, and inherited metabolic diseases.

INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES (2021)

Article Oncology

Safety, PK/PD and preliminary anti-tumor activities of pegylated recombinant human arginase 1 (BCT-100) in patients with advanced arginine auxotrophic tumors

Paul N. M. Cheng et al.

Summary: The study found that BCT-100 is safe and has anti-tumor activities in non-Chinese populations with MM and CRPC, with the optimal biological dose for future clinical phase II studies determined as 2.7 mg/kg weekly. Therapeutic Arginine Depletion was observed in the 1.7 and 2.7 mg/kg/week cohorts where anti-tumor activities were also seen.

INVESTIGATIONAL NEW DRUGS (2021)

Article Oncology

Phase 1, pharmacogenomic, dose-expansion study of pegargiminase plus pemetrexed and cisplatin in patients with ASS1-deficient non-squamous non-small cell lung cancer

Peter W. Szlosarek et al.

Summary: The combination of ADI-PEG20 with Pem and Cis was well-tolerated and highly active in ASS1-deficient non-squamous NSCLC, although overall survival was poor. ASS1 loss was co-associated with p53 mutations, suggesting further evaluation of therapies incorporating pegargiminase in ASS1-deficient and treatment-refractory NSCLC.

CANCER MEDICINE (2021)

Review Oncology

Arginine Signaling and Cancer Metabolism

Chia-Lin Chen et al.

Summary: Arginine plays crucial roles in cancer cells as a signaling metabolite, epigenetic regulator, and mitochondrial modulator, with the suppression of ASS1 transcription being a potential effective strategy for cancer therapy.

CANCERS (2021)

Article Oncology

The prognostic and therapeutic implications of distinct patterns of argininosuccinate synthase 1 (ASS1) and arginase-2 (ARG2) expression by cancer cells and tumor stroma in non-small-cell lung cancer

Alexandra Giatromanolaki et al.

Summary: ARG2 and ASS1 enzymes are extensively expressed in NSCLC stroma and cancer cells, respectively. Auxotrophic tumors have a poor prognosis, potentially by utilizing Arg, thus reducing Arg-dependent TIL anti-tumor activity. ASS1 expression in cancer cells would allow Arg fueling of (iNOS+)TILs and enhance anti-tumor immunity. However, upregulation of ARG2 in CAFs may divert Arg from TILs, allowing immune escape. Identification of these three distinct phenotypes may be useful in the individualization of Arg-targeting therapies and immunotherapy.

CANCER & METABOLISM (2021)

Article Oncology

Phase 1b study of pegylated arginine deiminase (ADI-PEG 20) plus Pembrolizumab in advanced solid cancers

Kwang-Yu Chang et al.

Summary: The study showed that the combination of ADI-PEG 20 and pembrolizumab is safe and feasible, but may lead to neutropenia. ADI-PEG 20 treatment increased T cell infiltration in the tumor microenvironment with low PD-L1 expression.

ONCOIMMUNOLOGY (2021)

Article Biochemistry & Molecular Biology

Arginine deprivation inhibits pancreatic cancer cell migration, invasion and EMT via the down regulation of Snail, Slug, Twist, and MMP1/9

Huan Wang et al.

JOURNAL OF PHYSIOLOGY AND BIOCHEMISTRY (2020)

Review Endocrinology & Metabolism

A non-proliferative role of pyrimidine metabolism in cancer

Aarif Siddiqui et al.

MOLECULAR METABOLISM (2020)

Review Oncology

Modulating pyrimidine ribonucleotide levels for the treatment of cancer

Tanzina Mollick et al.

CANCER & METABOLISM (2020)

Article Biochemistry & Molecular Biology

METTL14-mediated N6-methyladenosine modification of SOX4 mRNA inhibits tumor metastasis in colorectal cancer

Xiaoxiang Chen et al.

MOLECULAR CANCER (2020)

Review Biochemistry & Molecular Biology

Molecular Mechanisms of Nitric Oxide in Cancer Progression, Signal Transduction, and Metabolism

Veena Somasundaram et al.

ANTIOXIDANTS & REDOX SIGNALING (2019)

Article Oncology

MYC-Driven Small-Cell Lung Cancer is Metabolically Distinct and Vulnerable to Arginine Depletion

Milind D. Chalishazar et al.

CLINICAL CANCER RESEARCH (2019)

Article Biochemistry & Molecular Biology

Argininosuccinate Synthase 1 is a Metabolic Regulator of Colorectal Cancer Pathogenicity

Leslie A. Bateman et al.

ACS CHEMICAL BIOLOGY (2017)

Review Cell Biology

The Emerging Hallmarks of Cancer Metabolism

Natalya N. Pavlova et al.

CELL METABOLISM (2016)

Article Multidisciplinary Sciences

Diversion of aspartate in ASS1-deficient tumours fosters de novo pyrimidine synthesis

Shiran Rabinovich et al.

NATURE (2015)

Review Chemistry, Medicinal

Cellular and physiological effects of arginine

BC Tong et al.

MINI-REVIEWS IN MEDICINAL CHEMISTRY (2004)