Multiomic analysis identifies CPT1A as a potential therapeutic target in platinum-refractory, high-grade serous ovarian cancer

Huang, Dongqing; Chowdhury, Shrabanti; Wang, Hong; Savage, Sara R.; Ivey, Richard G.; Kennedy, Jacob J.; Whiteaker, Jeffrey R.; Lin, Chenwei; Hou, Xiaonan; Oberg, Ann L.; Larson, Melissa C.; Eskandari, Najmeh; Delisi, Davide A.; Gentile, Sandro; Huntoon, Catherine J.; Voytovich, Uliana J.; Shire, Zahra; Yu, Qing; Gygi, Steven P.; Hoofnagle, Andrew N.; Herbert, Zachary T.; Lorentzen, Travis D.; Calinawan, Anna; Karnitz, Larry M.; Weroha, S. John; Kaufmann, Scott H.; Zhang, Bing; Wang, Pei; Birrer, Michael J.; Paulovich, Amanda G.

doi:10.1016/j.xcrm.2021.100471

Cited by 33 publications

(45 citation statements)

References 190 publications

(252 reference statements)

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“…This would be particularly relevant in OC, since it has been extensively demonstrated that OXPHOS plays a relevant role in this tumor type compared to most cancers [ 50 ]. Accordingly, a recent multi-omic profiling of the same platinum-resistant and sensitive OC cell models used in the present study highlighted that OXPHOS and fatty acid oxidation are implicated in platinum resistance [ 28 ]. In recent years, evidence has been accumulating on the relevance of lipid metabolism in disease progression and acquisition of chemoresistance in OC [ 29 , 56 , 57 ].…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, metastatic OC cells in the omentum, growing in close proximity with adipocytes, enhance fatty acid uptake, by upregulating fatty acid receptor CD36, and utilization via β-oxidation, by upregulating the expression of CPT1A, leading to an increase in OXPHOS activity [ 25 , 26 ]. Notably, inhibition of both OXPHOS and β-oxidation improves the sensitivity of OC cells to platinum compounds [ 27 , 28 ]. In line with this evidence, we have previously demonstrated that drug resistant OC cells rely on OXPHOS for their energetic metabolism and that increased mitochondrial respiration is responsible for the chemoresistant phenotype by promoting the activation of a pro-inflammatory program [ 27 ].…”

Section: Introductionmentioning

confidence: 99%

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Decreased Levels of GSH Are Associated with Platinum Resistance in High-Grade Serous Ovarian Cancer

et al. 2022

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High-grade serous ovarian cancer (HGSOC) is the most common and aggressive OC histotype. Although initially sensitive to standard platinum-based chemotherapy, most HGSOC patients relapse and become chemoresistant. We have previously demonstrated that platinum resistance is driven by a metabolic shift toward oxidative phosphorylation via activation of an inflammatory response, accompanied by reduced cholesterol biosynthesis and increased uptake of exogenous cholesterol. To better understand metabolic remodeling in OC, herein we performed an untargeted metabolomic analysis, which surprisingly showed decreased reduced glutathione (GSH) levels in resistant cells. Accordingly, we found reduced levels of enzymes involved in GSH synthesis and recycling, and compensatory increased expression of thioredoxin reductase. Cisplatin treatment caused an increase of reduced GSH, possibly due to direct binding hindering its oxidation, and consequent accumulation of reactive oxygen species. Notably, expression of the cysteine-glutamate antiporter xCT, which is crucial for GSH synthesis, directly correlates with post-progression survival of HGSOC patients, and is significantly reduced in patients not responding to platinum-based therapy. Overall, our data suggest that cisplatin treatment could positively select cancer cells which are independent from GSH for the maintenance of redox balance, and thus less sensitive to cisplatin-induced oxidative stress, opening new scenarios for the GSH pathway as a therapeutic target in HGSOC.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Decreased Levels of GSH Are Associated with Platinum Resistance in High-Grade Serous Ovarian Cancer

et al. 2022

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“…CPT1A catalyzes the rate-limiting step of the fatty acid oxidation (FAO) pathway, promoting cell proliferation and suppressing apoptosis (42). Abnormal CPT1A expression was associated with the poor OS of AML (43), ovarian cancer (44), and glioblastoma stem cells (45). Leslimar et al reported that CPT1A could regulate prostate cancer survival in hypoxic conditions and promote aggressiveness (46).…”

Section: Discussionmentioning

confidence: 99%

Identification of a Mitochondria-Related Gene Signature to Predict the Prognosis in AML

et al. 2022

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Mitochondria-related metabolic reprogramming plays a major role in the occurrence, development, drug resistance, and recurrence of acute myeloid leukemia (AML). However, the roles of mitochondria-related genes (MRGs) in the prognosis and immune microenvironment for AML patients remain largely unknown. In this study, by least absolute shrinkage and selection operator (LASSO) Cox regression analysis, 4 MRGs’ (HPDL, CPT1A, IDH3A, and ETFB) signature was established that demonstrated good robustness in TARGET AML datasets. The univariate and multivariate Cox regression analyses both demonstrated that the MRG signature was a robust independent prognostic factor in overall survival prediction with high accuracy for AML patients. Based on the risk score calculated by the signature, samples were divided into high- and low-risk groups. Gene set enrichment analysis (GSEA) suggested that the MRG signature is involved in the immune-related pathways. Via immune infiltration analysis and immunosuppressive genes analysis, we found that MRG risk of AML patients was strikingly positively correlated with an immune cell infiltration and expression of critical immune checkpoints, indicating that the poor prognosis might be caused by immunosuppressive tumor microenvironment (TME). In summary, the signature based on MRGs could act as an independent risk factor for predicting the clinical prognosis of AML and could also reflect an association with the immunosuppressive microenvironment, providing a novel method for AML metabolic and immune therapy based on the regulation of mitochondrial function.

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“…Briefly, the pipeline consists of two major steps. We first derive prior information on causal protein-protein interactions using a time-course ovarian cancer cell line proteogenomic data set from a treatment perturbation experiment (Step 1) [26]. Then, using the direction information learned from Step 1 as priors, we construct an outcome-driven-DAG for genes in the Oxidative Phosphorylation and Adipogenesis pathways using a tumor proteogenomic data set from the CPTAC retrospective ovarian (Retro-Ova) cancer study (Step 2) [3].…”

Section: Application To Ovarian Cancermentioning

confidence: 99%

DAGBagM: learning directed acyclic graphs of mixed variables with an application to identify protein biomarkers for treatment response in ovarian cancer

Chowdhury

Wang

et al. 2022

BMC Bioinformatics

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Background Applying directed acyclic graph (DAG) models to proteogenomic data has been shown effective for detecting causal biomarkers of complex diseases. However, there remain unsolved challenges in DAG learning to jointly model binary clinical outcome variables and continuous biomarker measurements. Results In this paper, we propose a new tool, DAGBagM, to learn DAGs with both continuous and binary nodes. By using appropriate models, DAGBagM allows for either continuous or binary nodes to be parent or child nodes. It employs a bootstrap aggregating strategy to reduce false positives in edge inference. At the same time, the aggregation procedure provides a flexible framework to robustly incorporate prior information on edges. Conclusions Through extensive simulation experiments, we demonstrate that DAGBagM has superior performance compared to alternative strategies for modeling mixed types of nodes. In addition, DAGBagM is computationally more efficient than two competing methods. When applying DAGBagM to proteogenomic datasets from ovarian cancer studies, we identify potential protein biomarkers for platinum refractory/resistant response in ovarian cancer. DAGBagM is made available as a github repository at https://github.com/jie108/dagbagM.

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Multiomic analysis identifies CPT1A as a potential therapeutic target in platinum-refractory, high-grade serous ovarian cancer

Cited by 33 publications

References 190 publications

Decreased Levels of GSH Are Associated with Platinum Resistance in High-Grade Serous Ovarian Cancer

Decreased Levels of GSH Are Associated with Platinum Resistance in High-Grade Serous Ovarian Cancer

Identification of a Mitochondria-Related Gene Signature to Predict the Prognosis in AML

DAGBagM: learning directed acyclic graphs of mixed variables with an application to identify protein biomarkers for treatment response in ovarian cancer

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