Cited by 67Cancer Research and TreatmentsAmino Acid Enzymes and MetabolismHepatocellular Carcinoma Treatment and Prognosis

Down-regulation of argininosuccinate synthetase is associated with cisplatin resistance in hepatocellular carcinoma cell lines: implications for PEGylated arginine deiminase combination therapy

Open access
McAlpine, Jennifer A, Lu, Hsin-Tze, Wu, Katherine C, Knowles, Susan K, Thomson, James A·2014·BMC Cancer

Abstract

BACKGROUND: Many advanced human tumors, including hepatocellular carcinomas (HCC) are auxotrophic for arginine due to down-regulation of argininosuccinate synthetase (ASS1), the rate-limiting enzyme in arginine synthesis. The arginine-lowering agent PEGylated arginine deiminase (ADI-PEG 20) has shown efficacy as a monotherapy in clinical trials for treating arginine-auxotrophic tumors and is currently being evaluated in combination with cisplatin in other cancer types. Epigenetic silencing via methylation of the ASS1 promoter has been previously demonstrated in other cancer types, and a reciprocal relationship between ASS1 expression and cisplatin resistance has also been observed in ovarian cancer. However, the mechanism of ASS1 down-regulation, as well as the correlation with cisplatin resistance has not been explored in HCC. The present study investigates ADI-PEG 20 and cisplatin sensitivities in relation to ASS1 expression in HCC. In addition, we show how this biomarker is regulated by cisplatin alone and in combination with ADI-PEG 20. METHODS: ASS1 protein expression in both untreated and drug treated human HCC cell lines was assessed by western blot. The correlation between ASS1 protein levels, ADI-PEG 20 sensitivity and cisplatin resistance in these cell lines was established using a luminescence-based cell viability assay. Epigenetic regulation of ASS1 was analyzed by bisulfite conversion and methylation-specific PCR. RESULTS: A good correlation between absence of ASS1 protein expression, ASS1 promoter methylation, sensitivity to ADI-PEG 20 and resistance to cisplatin in HCC cell lines was observed. In addition, cisplatin treatment down-regulated ASS1 protein expression in select HCC cell lines. While, at clinically relevant concentrations, the combination of ADI-PEG 20 and cisplatin restored ASS1 protein levels in most of the cell lines studied. CONCLUSION: ASS1 silencing in HCC cell lines is associated with simultaneous cisplatin resistance and ADI-PEG 20 sensitivity which suggests a promising combination therapeutic strategy for the management of HCC.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1186/1471-2407-14-621

Cites

48 of 48 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Reduced expression of ASS1 and ASL is associated with poor prognosis and resistance to chemotherapy.

    “Reduced expression of ASS1 and ASL are associated with poor prognosis and resistance to chemotherapy (McAlpine et al., 2014; Nicholson et al., 2009).”

    From The emerging hallmarks of cancer metabolism (2016) · cites this paper as McAlpine et al., 2014

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Cites

Flagged first, then by citations

Research works printed but not linked: 1

  1. The pre-publication history for this paper can be accessed here: http://www.biomedcentral.com/1471-2407/14/621/prepub

Cited by

Sorted by citations

Authors
McAlpine, J. A., Lu, H.-T., Wu, K. C., Knowles, S. K., & Thomson, J. A.
Affiliations
Polarix (United States) (US)
Corresponding author
McAlpine, Jennifer A
Venue
BMC Cancer
Published
2014-08-28
Volume
14
Issue
1
Pages
621-621
ISSN
1471-2407 (ISSN-L)
OpenAlex
W1987246871
Cited by
67
References
48
Citations by year
2026: 5 · 2025: 9 · 2024: 3 · 2023: 2 · 2022: 4 · 2021: 10 · 2020: 7 · 2019: 5 · 2018: 9 · 2017: 4 · 2016: 7 · 2015: 2
FWCI
3.68
Type
journal article
Language
en
Open access
Locations
  • BMC Cancer (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Biotechnology › Cancer Research and Treatments
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Amino Acid Enzymes and Metabolism
  • Health Sciences › Medicine › Hepatology › Hepatocellular Carcinoma Treatment and Prognosis
Keywords
argininosuccinate synthetase, ASS1, cisplatin resistance, hepatocellular carcinoma, pegylated arginine deiminase, arginine auxotrophy, promoter methylation, epigenetic silencing, combination therapy, drug sensitivity biomarkers
MeSH terms
Antineoplastic Agents, Antineoplastic Combined Chemotherapy Protocols, Argininosuccinate Synthase, Cisplatin, Drug Synergism, Carcinoma, Hepatocellular, Humans, Hydrolases, Liver Neoplasms, Polyethylene Glycols, Drug Resistance, Neoplasm, DNA Methylation, Cell Line, Tumor, Hep G2 Cells

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review