Combination therapies induce cancer cell death through the integrated stress response and disturbed pyrimidine metabolism

Hartleben, Goetz; Schorpp, Kenji; Kwon, Yongseok; Betz, Barbara; Tsokanos, Foivos-Filippos; Dantes, Zahra; Schäfer, A; Rothenaigner, Ina; Kuhn, José Manuel Monroy; Morigny, Pauline; Mehr, Lisa; Lin, Sean; Seitz, Susanne; Tokarz, Janina; Artati, Anna; Adamsky, Jerzy; Plettenburg, Oliver; Lutter, Dominik; Irmler, Martin; Beckers, Johannes; Reichert, Maximilian; Hadian, Kamyar; Zeigerer, Anja; Herzig, Stephan; Díaz, Mauricio Berriel

doi:10.15252/emmm.202012461

Cited by 13 publications

(7 citation statements)

References 46 publications

(54 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The combination of mitochondrial uncoupler niclosamide ethanolamine and dopamine receptor antagonist domperidone or TCAs induces ISR and leas to apoptosis in multiple cancer cell lines including CRC, GBM (Glioblastoma multiforme) and PDAC (Pancreatic ductal adenocarcinoma) cell lines (Hartleben et al, 2021). Even without inducing apoptosis, the ISR is induced by ONC201 in cancer cells exhibiting decreased cell proliferation (Kline et al, 2016).…”

Section: Dual Roles Of the Integrated Stress Response In Cancermentioning

confidence: 99%

Targeting the Integrated Stress Response in Cancer Therapy

et al. 2021

View full text Add to dashboard Cite

The integrated stress response (ISR) is an evolutionarily conserved intra-cellular signaling network which is activated in response to intrinsic and extrinsic stresses. Various stresses are sensed by four specialized kinases, PKR-like ER kinase (PERK), general control non-derepressible 2 (GCN2), double-stranded RNA-dependent protein kinase (PKR) and heme-regulated eIF2α kinase (HRI) that converge on phosphorylation of serine 51 of eIF2α. eIF2α phosphorylation causes a global reduction of protein synthesis and triggers the translation of specific mRNAs, including activating transcription factor 4 (ATF4). Although the ISR promotes cell survival and homeostasis, when stress is severe or prolonged the ISR signaling will shift to regulate cellular apoptosis. We review the ISR signaling pathway, regulation and importance in cancer therapy.

show abstract

Section: Dual Roles Of the Integrated Stress Response In Cancermentioning

confidence: 99%

Targeting the Integrated Stress Response in Cancer Therapy

et al. 2021

View full text Add to dashboard Cite

show abstract

“…Intriguingly, DDIT4 (induced by metformin, p53, and p63) can form a complex with TXNIP to trigger cell death under oxidative stress [ 46 , 47 ]. UPP1 is a pyrimidine degrading enzyme that contributes to cancer cell death in response to drugs that induce lethal catabolic stress [ 48 ]. Finally, GADD34 is a pro-apoptotic gene induced by DNA damage, and is also regulated by ATF3 [ 49 , 50 ].…”

Section: Resultsmentioning

confidence: 99%

The NAMPT Inhibitor FK866 Increases Metformin Sensitivity in Pancreatic Cancer Cells

Parisotto

Vuong-Robillard

Kalegari

et al. 2022

Cancers

View full text Add to dashboard Cite

Pancreatic cancer (pancreatic ductal adenocarcinoma: PDAC) is one of the most aggressive neoplastic diseases. Metformin use has been associated with reduced pancreatic cancer incidence and better survival in diabetics. Metformin has been shown to inhibit PDAC cells growth and survival, both in vitro and in vivo. However, clinical trials using metformin have failed to reduce pancreatic cancer progression in patients, raising important questions about molecular mechanisms that protect tumor cells from the antineoplastic activities of metformin. We confirmed that metformin acts through inhibition of mitochondrial complex I, decreasing the NAD+/NADH ratio, and that NAD+/NADH homeostasis determines metformin sensitivity in several cancer cell lines. Metabolites that can restore the NAD+/NADH ratio caused PDAC cells to be resistant to metformin. In addition, metformin treatment of PDAC cell lines induced a compensatory NAMPT expression, increasing the pool of cellular NAD+. The NAMPT inhibitor FK866 sensitized PDAC cells to the antiproliferative effects of metformin in vitro and decreased the cellular NAD+ pool. Intriguingly, FK866 combined with metformin increased survival in mice bearing KP4 cell line xenografts, but not in mice with PANC-1 cell line xenografts. Transcriptome analysis revealed that the drug combination reactivated genes in the p53 pathway and oxidative stress, providing new insights about the mechanisms leading to cancer cell death.

show abstract

“…Cancer is believed to exhibite a fundamental trait of metabolic rewiring. Malignant cells alter their metabolic pathways in response to various intrinsic and extrinsic challenges to fuel cell survival and expansion ( 28 ). A vast body of evidence has shown that PyM failure is closely associated with cancer growth, and various medications targeting PyM have been authorized for a variety of cancers.…”

Section: Discussionmentioning

confidence: 99%

Pyrimidine metabolism regulator-mediated molecular subtypes display tumor microenvironmental hallmarks and assist precision treatment in bladder cancer

Wu,

Li,

et al. 2023

Front. Oncol.

View full text Add to dashboard Cite

BackgroundBladder cancer (BLCA) is a common urinary system malignancy with a significant morbidity and death rate worldwide. Non-muscle invasive BLCA accounts for over 75% of all BLCA cases. The imbalance of tumor metabolic pathways is associated with tumor formation and proliferation. Pyrimidine metabolism (PyM) is a complex enzyme network that incorporates nucleoside salvage, de novo nucleotide synthesis, and catalytic pyrimidine degradation. Metabolic reprogramming is linked to clinical prognosis in several types of cancer. However, the role of pyrimidine metabolism Genes (PyMGs) in the BLCA-fighting process remains poorly understood.MethodsPredictive PyMGs were quantified in BLCA samples from the TCGA and GEO datasets. TCGA and GEO provided information on stemness indices (mRNAsi), gene mutations, CNV, TMB, and corresponding clinical features. The prediction model was built using Lasso regression. Co-expression analysis was conducted to investigate the relationship between gene expression and PyM.ResultsPyMGs were overexpressed in the high-risk sample in the absence of other clinical symptoms, demonstrating their predictive potential for BLCA outcome. Immunological and tumor-related pathways were identified in the high-risk group by GSWA. Immune function and m6a gene expression varied significantly between the risk groups. In BLCA patients, DSG1, C6orf15, SOST, SPRR2A, SERPINB7, MYBPH, and KRT1 may participate in the oncology process. Immunological function and m6a gene expression differed significantly between the two groups. The prognostic model, CNVs, single nucleotide polymorphism (SNP), and drug sensitivity all showed significant gene connections.ConclusionsBLCA-associated PyMGs are available to provide guidance in the prognostic and immunological setting and give evidence for the formulation of PyM-related molecularly targeted treatments. PyMGs and their interactions with immune cells in BLCA may serve as therapeutic targets.

show abstract

Combination therapies induce cancer cell death through the integrated stress response and disturbed pyrimidine metabolism

Cited by 13 publications

References 46 publications

Targeting the Integrated Stress Response in Cancer Therapy

Targeting the Integrated Stress Response in Cancer Therapy

The NAMPT Inhibitor FK866 Increases Metformin Sensitivity in Pancreatic Cancer Cells

Pyrimidine metabolism regulator-mediated molecular subtypes display tumor microenvironmental hallmarks and assist precision treatment in bladder cancer

Contact Info

Product

Resources

About