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Glutamine metabolism controls amphiregulin-facilitated chemoresistance to cisplatin in human chondrosarcoma

ABSTRACT: Chondrosarcoma is the second most common type of bone cancer. At present, the most effective clinical course of action is surgical resection. Cisplatin is the chemotherapeutic medication most widely used for the treatment of chondrosarcoma; however, its effectiveness is severely hampered by drug resistance. In the current study, we compared cisplatin-resistant chondrosarcoma SW1353 cells with their parental cells via RNA sequencing. Our analysis revealed that glutamine metabolism is highly activated in resistant cells but glucose metabolism is not. Amphiregulin (AR), a ligand of the epidermal growth factor receptor, enhances glutamine metabolism and supports cisplatin resistance in human chondrosarcoma by promoting NADPH production and inhibiting ROS accumulation. The MEK, ERK, and NrF2 signaling pathways were shown to regulate AR-mediated SLC1A5 and GLS expression as well as glutamine metabolism in cisplatin-resistant chondrosarcoma. The knockdown of AR expression in cisplatin-resistant chondrosarcoma cells was shown to reduce the expression of SLC1A5 and GLS in vivo. These results indicate that AR and glutamine metabolism are worth pursuing as therapeutic targets in dealing with cisplatin-resistant human chondrosarcoma.

ORGANISM(S): Homo sapiens

PROVIDER: GSE239911 | GEO | 2023/08/07

REPOSITORIES: GEO

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Glutamine metabolism controls amphiregulin-facilitated chemoresistance to cisplatin in human chondrosarcoma

Project description:Glutamine metabolism controls amphiregulin-facilitated chemoresistance to cisplatin in human chondrosarcoma

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Project description:Activated T cells differentiate into functional subsets which require distinct metabolic programs. Glutaminase (GLS) converts glutamine to glutamate to provide substrate for the tricarboxylic acid cycle and epigenetic reactions and here we identify a key role for GLS in T cell activation and specification. Though GLS-deficiency diminished T cell activation, proliferation and impaired differentiation of Th17 cells, loss of GLS also increased Tbet and Interferon-γ expression and CD4 Th1 and CD8 CTL effector cell differentiation. These changes were mediated by differentially altered gene expression and chromatin accessibility, leading to increased sensitivity of Th1 cells to IL-2 mediated mTORC1 signaling. In vivo, GLS-null T cells failed to drive a Th17 mediated Graft-vs-Host Disease model. Transient inhibition of GLS, however, increased Th1 and CTL T cell numbers in viral and chimeric antigen receptor models. Glutamine metabolism thus has distinct roles to promote Th17 but constrain Th1 and CTL effector cell differentiation.

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Inhibiting MYC-regulated Glutaminase Metabolic Axis is an Effective Synthetic Lethal Approach for Treating Chemoresistant Cancers

Project description:Amplification and expression 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. We have discovered that ovarian cancer cells overexpressing glutaminase (GLS), a MYC target and a key enzyme in glutaminolysis, are intrinsically resistant to platinum chemotherapy, and are enriched in the 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 low GLS-expressing ovarian cancer cells. Treatment with CB-839 rendered GLShigh 10 cells vulnerable to the poly(ADP-ribose) polymerase (PARP) inhibitor, olaparib, and prolonged survival in tumor-bearing mice. Our findings suggest that applying a combined therapy of GLS inhibitor and PARP inhibitor could effectively treat chemoresistant ovarian cancers, especially those with high GLS expression.

2020-07-23 | GSE154941 | GEO

Th1 and T17 activation with and without CB839 treatment

Project description:Activated T cells differentiate into functional subsets which require distinct metabolic programs. Glutaminase (GLS) converts glutamine to glutamate to provide substrate for the tricarboxylic acid cycle and epigenetic reactions and here we identify a key role for GLS in T cell activation and specification. Though GLS-deficiency diminished T cell activation, proliferation and impaired differentiation of Th17 cells, loss of GLS also increased Tbet and Interferon-γ expression and CD4 Th1 and CD8 CTL effector cell differentiation. These changes were mediated by differentially altered gene expression and chromatin accessibility, leading to increased sensitivity of Th1 cells to IL-2 mediated mTORC1 signaling. In vivo, GLS-null T cells failed to drive a Th17-mediated Graft-vs-Host Disease model. Transient inhibition of GLS, however, increased Th1 and CTL T cell numbers in viral and chimeric antigen receptor models. Glutamine metabolism thus has distinct roles to promote Th17 but constrain Th1 and CTL effector cell differentiation.

2019-02-13 | GSE112244 | GEO

The unique catalytic properties of PSAT1 mediate metabolic adaptation to glutamine blockade

Project description:Cultured cancer cells frequently rely on the consumption of glutamine and its subsequent hydrolysis to glutamate by the mitochondrial enzyme glutaminase (GLS). However, this metabolic addiction can be lost in the tumor microenvironment (TME), rendering GLS inhibitors ineffective in the clinic. Here, we show that seemingly glutamine-addicted breast cancer cells ultimately adapt to chronic glutamine starvation, or targeted GLS inhibition, via the AMPK-mediated upregulation of the serine synthesis pathway (SSP). In this context, the key product of the SSP is not serine itself, but a-ketoglutarate (a-KG). Mechanistically, we find that the phylogenetically distinct transaminase phosphoserine aminotransferase 1 (PSAT1) has a unique capacity for sustained a-KG production when glutamate is severely depleted. Breast cancer cells with intrinsic or acquired resistance to glutamine starvation or GLS inhibition are highly dependent on SSP-supplied a-KG. Accordingly, pharmacological disruption of the SSP prevents adaptation to glutamine blockade, yielding a potent drug synergism that abolishes breast tumor growth in vivo. These findings highlight how metabolic redundancy can be context dependent, with the catalytic properties of different metabolic enzymes that act on the same substrate determining which pathways can support tumor growth in a particular nutrient environment. This in turn has practical consequences for therapies targeting cancer metabolism.

2024-07-05 | GSE263696 | GEO

Brain tumor stem cell dependence on glutaminase reveals a metabolic vulnerability through the amino acid deprivation response pathway

Project description:Cancer cells can metabolize glutamine to replenish TCA cycle intermediates, leading to a dependence on glutaminolysis for cell survival. However, a mechanistic understanding of the role that glutamine metabolism has on the survival of glioblastoma (GBM) brain tumor stem cells (BTSCs) has not yet been elucidated. Here we report that, across a panel of twenty glioblastoma BTSC lines, glutaminase (GLS) inhibition showed a variable response – from complete blockade of cell growth to absolute resistance. Surprisingly, BTSC sensitivity to GLS inhibition was a result of reduced intracellular glutamate triggering the amino acid deprivation response (AADR) and not due to the contribution of glutaminolysis to the TCA cycle. Moreover, BTSC sensitivity to GLS inhibition negatively correlated with the expression of the astrocytic glutamate transporters EAAT1 and EAAT2. Blocking glutamate transport in BTSCs with high EAAT1/EAAT2 expression rendered these cells susceptible to GLS inhibition, triggering the AADR, and limiting cell growth. These findings uncover a unique metabolic vulnerability in BTSCs, support the therapeutic targeting of the upstream activators and downstream effectors of the AADR pathway in GBM, and demonstrate that gene expression patterns reflecting the cellular hierarchy of the tissue of origin can alter the metabolic requirements of the cancer stem cell population.

2020-12-25 | GSE155300 | GEO

Glutaminolysis is a metabolic dependency in FLT3 ITD Acute Myeloid Leukemia unmasked by FLT3 Tyrosine Kinase Inhibition

Project description:FLT3ITD are common mutations in Acute Myeloid Leukemia (AML) and carry a particularly bad prognosis. Although new generation FLT3 tyrosine kinase inhibitors (TKI) have shown promising results, the outcome of FLT3-mutated AML patients remains poor and demands the identification of novel, specific and validated therapeutic targets for this highly aggressive AML subtype. Utilizing an unbiased genome-wide CRISPR/Cas9 screen, we identify GLS, the first enzyme in glutamine metabolism, as synthetically lethal with FLT3 TKI treatment. Using complementary metabolomic and gene-expression analysis, we demonstrate that glutamine metabolism, through its ability to support both mitochondrial function and cellular redox metabolism, becomes a metabolic dependency of FLT3ITD AML, specifically unmasked by FLT3-TKI treatment. We extend these findings to AML subtypes driven by other tyrosine kinase activating mutations, and validate the role of GLS as a clinically actionable therapeutic target in both primary AML and in vivo models. Our work highlights the role of metabolic adaptations as a resistance mechanism to several TKI inhibitors, and suggests glutaminolysis as a therapeutically targetable vulnerability when combined with specific TKI in FLT3ITD and other TK activating mutation driven leukemias.

2018-03-07 | GSE105161 | GEO

Genome-wide chromatin profiles of ZNF395 [RNA-seq]

Project description:Hypoxia signaling induced by VHL deficiency fuels growth but also poses immense metabolic stress to clear cell renal cell carcinomas (ccRCCs). Tumor cells depend on glutamine as the primary source of tricarboxylic acid (TCA) anaplerosis. Hypoxia-inducible factor alpha (HIFα) governs glycolysis but does not directly regulate glutamine metabolism; instead, the factor responsible for orchestrating glutamine metabolism and mitochondrial adaptations to hypoxia remains elusive. We now show that ZNF395 is a hypoxia-responsive factor that regulates glutamine metabolism in the mitochondria. ZNF395 is activated by a HIF2α-modulated super-enhancer but plays non-redundant functions from HIF2α. Specifically, ZNF395 facilitates the transcription of enzymes essential for glutaminolysis, including glutaminase (GLS) and isocitrate dehydrogenase 2 (IDH2). Functionally, ZNF395 depletion results in reduced TCA intermediates and their derivatives, including amino acids, glutathione and pyrimidine nucleotides. In addition, ZNF395 depletion diminishes mitochondrial respiration; restoration of complex I function rescues the effects of ZNF395 depletion. Our study underscores the coordinated role of HIFα and ZNF395 in shaping metabolic adaptations in response to hypoxia in VHL-deficient ccRCCs.

2024-10-01 | GSE247117 | GEO

Genome-wide chromatin profiles of ZNF395 [ChIP-seq]

2024-10-01 | GSE247116 | GEO

ASCT2 is a major contributor to serine uptake in cancer cells

Project description:The non-essential amino acid serine is a critical nutrient for cancer cells due to its diverse biosynthetic functions. While some tumors can synthesize serine de novo, others are auxotrophic and therefore reliant on serine uptake. Importantly, despite several transporters being known to be capable of transporting serine, the transporter(s) that mediate serine uptake in cancer cells are not known. Here, we characterize the amino acid transporter ASCT2 (SLC1A5) as a major contributor to serine uptake in cancer cells. ASCT2 is well-known as a glutamine transporter in cancer, and our work demonstrates that serine and glutamine compete for uptake through ASCT2. We further show that ASCT2-mediated serine uptake is essential for purine nucleotide biosynthesis and that ERα promotes serine uptake by directly activating SLC1A5 transcription. Together, our work defines an additional important role for ASCT2 as a serine transporter in cancer and evaluates ASCT2 as a potential therapeutic target.

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