Role of CPS1 in Cell Growth, Metabolism, and Prognosis in LKB1-Inactivated Lung Adenocarcinoma

Çeliktaş, Müge; Tanaka, Ichidai; Tripathi, Satyendra Chandra; Fahrmann, Johannes F.; Aguilar-Bonavides, Clemente; Villalobos, Pamela; Delgado, Oliver; Dhillon, Dilsher; Dennison, Jennifer B.; Ostrin, Edwin J.; Wang, Hong; Behrens, Carmen; Anh, Kim; Gazdar, Adi F.; Hanash, Samir M.; Taguchi, Ayumu

doi:10.1093/jnci/djw231

Cited by 74 publications

(84 citation statements)

References 54 publications

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“…It has been shown that in human lung adenocarcinoma (LADC), CPS1 mRNA expression was highest in tumors with LKB1 loss (24). Similarly, LADC with LKB1 loss exhibited higher CPS1 protein expression by analyzing a tissue microarray (23). Furthermore, high expression of CPS1 was found to be associated with worse overall survival.…”

Section: Association Of Cps1 Expression With Lung Adenocarcinoma Patimentioning

confidence: 99%

“…Carbamoyl phosphate plays a crucial role in arginine metabolism and pyrimidine biosynthesis, serving as a precursor for both processes (22). CPS1 has been shown to play a role in metabolism and cell growth of LKB1-inactivated lung adenocarcinomas and CPS1 expression in lung adenocarcinoma tumors has been associated with worse overall survival (23). Mechanistically, CPS1 has been shown to sustain pyrimidine levels and DNA synthesis in KRAS/LKB1 lung cancer cells (24).…”

Section: Introductionmentioning

confidence: 99%

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Urea Cycle Sustains Cellular Energetics upon EGFR Inhibition in EGFR-Mutant NSCLC

Pham-Danis

Gehrke

Danis

et al. 2019

Molecular Cancer Research

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Mutations in oncogenes and tumor suppressor genes engender unique metabolic phenotypes crucial to the survival of tumor cells. EGFR signaling has been linked to the rewiring of tumor metabolism in non-small cell lung cancer (NSCLC). We have integrated the use of a functional genomics screen and metabolomics to identify metabolic vulnerabilities induced by EGFR inhibition. These studies reveal that following EGFR inhibition, EGFR-driven NSCLC cells become dependent on the urea cycle and, in particular, the urea cycle enzyme CPS1. Combining knockdown of CPS1 with EGFR inhibition further reduces cell proliferation and impedes cell-cycle progression. Profiling of the metabolome demonstrates that suppression of CPS1 potentiates the effects of EGFR inhibition on central carbon metabolism, pyrimidine biosynthesis, and arginine metabolism, coinciding with reduced glycolysis and mitochondrial respiration. We show that EGFR inhibition and CPS1 knockdown lead to a decrease in arginine levels and pyrimidine derivatives, and the addition of exogenous pyrimidines partially rescues the impairment in cell growth. Finally, we show that high expression of CPS1 in lung adenocarcinomas correlated with worse patient prognosis in publicly available databases. These data collectively reveal that NSCLC cells have a greater dependency on the urea cycle to sustain central carbon metabolism, pyrimidine biosynthesis, and arginine metabolism to meet cellular energetics upon inhibition of EGFR.Implications: Our results reveal that the urea cycle may be a novel metabolic vulnerability in the context of EGFR inhibition, providing an opportunity to develop rational combination therapies with EGFR inhibitors for the treatment of EGFRdriven NSCLC. Analysis and interpretation of data (e.g., statistical analysis, biostatistics, computational analysis): C. Pham-Danis, S.

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Section: Association Of Cps1 Expression With Lung Adenocarcinoma Patimentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Urea Cycle Sustains Cellular Energetics upon EGFR Inhibition in EGFR-Mutant NSCLC

Pham-Danis

Gehrke

Danis

et al. 2019

Molecular Cancer Research

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“…LKB1-mutant cells showed a decrease in AMPK phosphorylation even upon treatment with a known AMPK activator AICAR which is an intermediate of the purine biosynthesis pathway acted upon by ATIC, the rate-limiting enzyme of this pathway (126). Inducing overexpression of CPS1 in LKB1-inactivated lung adenocarcinoma cell lines or CPS1-negative lung adenocarcinoma cell lines did not induce cell growth (121). This suggested that the role played by CPS1in cell growth might be complemented by other genes in CPS1-negative cell lines.…”

Section: Novel Interactions Of Atic May Underlie Malignant Transformamentioning

confidence: 97%

“…CPS1 is a mitochondrial enzyme that catalyzes the first committed step of the urea cycle and is critical in preventing accumulation of toxic ammonia. When CPS1 is knocked down in LKB1-inactivated lung adenocarcinoma cells, there was a reduction in the level of metabolites associated with purine synthesis, and in cell growth (121). LKB1is a master kinase found to be mutated in 20% of non-small cell lung cancers and in mesothelioma cell lines.…”

Section: Novel Interactions Of Atic May Underlie Malignant Transformamentioning

confidence: 99%

“…This suggested that the role played by CPS1in cell growth might be complemented by other genes in CPS1-negative cell lines. CPS1 overexpression in LKB1-inactivated cells failing to induce cell growth may indicate that purine biosynthesis (even though shown to be affected by CPS1 knockdown) was regulated differently in cancer cells (121). The fact that the treatment of LKB1-mutant cells with AICAR failed to activate AMPK, which is necessary for inactivation of the purine biosynthesis pathway and thereby control of cell growth, might also point at a different pathway or set of interactions regulating purine biosynthesis and growth of these cancerous cells (126).…”

Section: Novel Interactions Of Atic May Underlie Malignant Transformamentioning

confidence: 99%

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Mesothelioma Interactome with 367 Novel Protein-Protein Interactions

Yanamala

Boyce

et al. 2018

Preprint

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Malignant pleural mesothelioma (MPM) is an aggressive cancer of the thorax with a median survival of one year. We constructed an 'MPM interactome' with over 300 computationally predicted PPIs and over 1300 known PPIs of 62 literature-curated genes whose activity affects MPM. Known PPIs of the 62 MPM associated genes were derived from BioGRID and HPRD databases. Novel PPIs were predicted by applying the HiPPIP algorithm, which computes features of protein pairs such as cellular localization, molecular function, biological process membership, genomic location of the gene, gene expression in microarray experiments, protein domains and tissue membership, and classifies the pairwise features as interacting or non-interacting based on a random forest model. To our satisfaction, the interactome is significantly enriched with genes differentially expressed in MPM tumors compared with normal pleura, and with other thoracic tumors. The interactome is also significantly enriched with genes whose high expression has been correlated with unfavorable prognosis in lung cancer, and with genes differentially expressed on crocidolite exposure. 28 of the interactors of MPM proteins are targets of 147 FDA-approved drugs. By comparing differential expression profiles induced by drug to profiles induced by MPM, potentially repurposable drugs are identified from this drug list. Development of PPIs of disease-specific set of genes is a powerful approach with high translational impactthe interactome is a vehicle to piece together an integrated view on how genes associated with MPM through various high throughput studies are functionally linked, leading to clinically translatable results such as clinical trials with repurposed drugs. The PPIs are made available on a webserver, called Wiki-Pi MPM at http://severus.dbmi.pitt.edu/wiki-MPM with advanced search capabilities.Recently, twenty four germline mutations were identified in 13 genes from 198 patients with malignant mesothelioma of pleural or peritoneal origin (11). Non-invasive pre-malignant phase is not seen in mesothelioma unlike other tumors, which necessitates expeditious discovery of genetic predispositions, molecular mechanisms and therapeutics for the disease (12).60% of the disease-associated missense mutations perturb protein-protein interactions (PPIs) in human genetic disorders (13). PPIs are intricately involved in biological functions and disease mechanisms, and may be exploited for drug-discovery (13). The molecular mechanisms of disease are often revealed by the PPIs of diseaseassociated genes. For example, the involvement of transcriptional deregulation in the pathogenesis of MPM was identified through mutations detected in BAP1 and its interactions with several proteins including BRCA1 revealed by co-immunoprecipitation (14). The PPI of BRCA1 with BAP1 was also central in understanding its role in growth-control pathways and cancer (15). Studies on BAP1 and BRCA1 later provided the basis for several clinical trials including testing of the drug Vinorelbine as a second...

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Proteomic analysis enables distinction of early‐ versus advanced‐stage lung adenocarcinomas

Kelemen

Plá

Sánchez

et al. 2020

Clinical & Translational Med

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Background A gel‐free proteomic approach was utilized to perform in‐depth tissue protein profiling of lung adenocarcinoma (ADC) and normal lung tissues from early and advanced stages of the disease. The long‐term goal of this study is to generate a large‐scale, label‐free proteomics dataset from histologically well‐classified lung ADC that can be used to increase further our understanding of disease progression and aid in identifying novel biomarkers. Methods and results Cases of early‐stage (I‐II) and advanced‐stage (III‐IV) lung ADCs were selected and paired with normal lung tissues from 22 patients. The histologically and clinically stratified human primary lung ADCs were analyzed by liquid chromatography‐tandem mass spectrometry. From the analysis of ADC and normal specimens, 4863 protein groups were identified. To examine the protein expression profile of ADC, a peak area‐based quantitation method was used. In early‐ and advanced‐stage ADC, 365 and 366 proteins were differentially expressed, respectively, between normal and tumor tissues (adjusted P ‐value < .01, fold change ≥ 4). A total of 155 proteins were dysregulated between early‐ and advanced‐stage ADCs and 18 were suggested as early‐specific stage ADC. In silico functional analysis of the upregulated proteins in both tumor groups revealed that most of the enriched pathways are involved in mRNA metabolism. Furthermore, the most overrepresented pathways in the proteins that were unique to ADC are related to mRNA metabolic processes. Conclusions Further analysis of these data may provide an insight into the molecular pathways involved in disease etiology and may lead to the identification of biomarker candidates and potential targets for therapy. Our study provides potential diagnostic biomarkers for lung ADC and novel stage‐specific drug targets for rational intervention.

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Role of CPS1 in Cell Growth, Metabolism, and Prognosis in LKB1-Inactivated Lung Adenocarcinoma

Cited by 74 publications

References 54 publications

Urea Cycle Sustains Cellular Energetics upon EGFR Inhibition in EGFR-Mutant NSCLC

Urea Cycle Sustains Cellular Energetics upon EGFR Inhibition in EGFR-Mutant NSCLC

Mesothelioma Interactome with 367 Novel Protein-Protein Interactions

Proteomic analysis enables distinction of early‐ versus advanced‐stage lung adenocarcinomas

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