Inhibiting MYC-regulated Glutaminase Metabolic Axis is an Effective Synthetic Lethal Approach for Treating Chemoresistant Cancers
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA647915 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR12300156.fastq.gz | Fastqsanger.gz | |||
| SRR12300157.fastq.gz | Fastqsanger.gz | |||
| SRR12300158.fastq.gz | Fastqsanger.gz | |||
| SRR12300159.fastq.gz | Fastqsanger.gz |
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Project description:Amplification and overexpression of the MYC oncogene in tumor cells, including ovarian cancer cells, correlates with poor responses to chemotherapy. As MYC is not directly targetable, we have analyzed molecular pathways downstream of MYC to identify potential therapeutic targets. Here we report that ovarian cancer cells overexpressing glutaminase (GLS), a target of MYC and a key enzyme in glutaminolysis, are intrinsically resistant to platinum-based chemotherapy and are enriched with intracellular antioxidant glutathione. Deprivation of glutamine by glutamine-withdrawal, GLS knockdown, or exposure to the GLS inhibitor CB-839 resulted in robust induction of reactive oxygen species in high GLS-expressing but not in low GLS-expressing ovarian cancer cells. Treatment with CB-839 rendered GLShigh cells vulnerable to the poly(ADP-ribose) polymerase (PARP) inhibitor, olaparib, and prolonged survival in tumor-bearing mice. These findings suggest consideration of applying a combined therapy of GLS inhibitor and PARP inhibitor to treat chemoresistant ovarian cancers, especially those with high GLS expression. SIGNIFICANCE: Targeting glutaminase disturbs redox homeostasis and nucleotide synthesis and causes replication stress in cancer cells, representing an exploitable vulnerability for the development of effective therapeutics. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/80/20/4514/F1.large.jpg.
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Project description:Many cases of advanced hepatocellular carcinoma (HCC) are resistant to the widely used drug sorafenib, which worsens prognosis. While many studies have explored how acquired resistance emerges during drug exposure, the mechanism underlying primary resistance before treatment still remain elusive. Here, we performed single-cell lineage tracing and RNA sequencing to identify sorafenib-resistant lineages in HCC, and demonstrated that high expression of S100A14 was positively associated with primary sorafenib resistance. Knocking down S100A14 rendered xenograft tumors in mice significantly more sensitive to sorafenib. Mechanistic studies indicated that S100A14 binds to glutaminase and blocks its phosphorylation at residues Y308 and S314, which in turn inhibits its ubiquitination and subsequent degradation. This stabilization of glutaminase reduces oxidative stress in HCC cells and thereby antagonizes the ability of sorafenib to induce apoptosis. Inhibiting glutaminase with telaglenastat (CB-839) significantly improved sorafenib efficacy against xenograft tumors in vivo. These results suggest that S100A14 can contribute to primary sorafenib resistance in HCC by stabilizing glutaminase. Thus, analyzing the expression of S100A14 may be useful for predicting primary sorafenib resistance, and inhibiting S100A14 or glutaminase may be effective for preventing or overcoming such resistance.
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Project description:The gene GLS generates the phosphate activated glutaminase C (GAC) isoform by alternative splicing. GAC, compared to the other isoform, kidney-type glutaminase (KGA), has been characterized as more active and particularly important for cancer cell growth. Very little is known about post-translational modifications regulating GAC function. Hereby we describe the identification of a phosphorylation on the serine 95, located at the GLS N-terminus, a domain shared by both isoforms. A GAC phosphomimetic mutant (S95D) ectopically expressed in breast cancer cells presented decreased enzymatic activity, and its expression impacted on cell’s glutamine uptake, glutamate release and intracellular glutamate levels (compared to expressing wild type GAC) without changing GAC sub-cellular localization. Curiously, replacing S95 by an alanine in the ectopically expressed GAC (S95A) increased cell proliferation and migration. Taken together, these results reveal that GAC is post-translationally regulated by phosphorylation, which impacts on cancer phenotype.
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