Dataset Information

Multiomic Profiling of Tyrosine Kinase Inhibitor-Resistant K562 Cells Suggests Metabolic Reprogramming To Promote Cell Survival.

ABSTRACT: Resistance to chemotherapy can occur through a wide variety of mechanisms. Resistance to tyrosine kinase inhibitors (TKIs) often arises from kinase mutations-however, "off-target" resistance occurs but is poorly understood. Previously, we established cell line resistance models for three TKIs used in chronic myeloid leukemia treatment, and found that resistance was not attributed entirely to failure of kinase inhibition. Here, we performed global, integrated proteomic and transcriptomic profiling of these cell lines to describe mechanisms of resistance at the protein and gene expression level. We used whole transcriptome sequencing and SWATH-based data-independent acquisition mass spectrometry (DIA-MS), which does not require isotopic labels and provides quantitative measurements of proteins in a comprehensive, unbiased fashion. The proteomic and transcriptional data were correlated to generate an integrated understanding of the gene expression and protein alterations associated with TKI resistance. We defined mechanisms of resistance and two novel markers, CA1 and alpha-synuclein, that were common to all TKIs tested. Resistance to all of the TKIs was associated with oxidative stress responses, hypoxia signatures, and apparent metabolic reprogramming of the cells. Metabolite profiling and glucose-dependence experiments showed that resistant cells had routed their metabolism through glycolysis (particularly through the pentose phosphate pathway) and exhibited disruptions in mitochondrial metabolism. These experiments are the first to report a global, integrated proteomic, transcriptomic, and metabolic analysis of TKI resistance. These data suggest that although the mechanisms are complex, targeting metabolic pathways along with TKI treatment may overcome pan-TKI resistance.

SUBMITTER: Noel BM

PROVIDER: S-EPMC7250065 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Multiomic Profiling of Tyrosine Kinase Inhibitor-Resistant K562 Cells Suggests Metabolic Reprogramming To Promote Cell Survival.

Noel Brett M BM Ouellette Steven B SB Marholz Laura L Dickey Deborah D Navis Connor C Yang Tzu-Yi TY Nguyen Vinh V Parker Sarah J SJ Bernlohr David D Sachs Zohar Z Parker Laurie L LL

Journal of proteome research 20190221 4

Resistance to chemotherapy can occur through a wide variety of mechanisms. Resistance to tyrosine kinase inhibitors (TKIs) often arises from kinase mutations-however, "off-target" resistance occurs but is poorly understood. Previously, we established cell line resistance models for three TKIs used in chronic myeloid leukemia treatment, and found that resistance was not attributed entirely to failure of kinase inhibition. Here, we performed global, integrated proteomic and transcriptomic profilin ...[more]

PMID: 30730747

Similar Datasets

Project description:There is increasing evidence that root exudates play important roles in plant disease resistance. Black shank, caused by Phytophthora nicotianae, is a destructive soil-borne disease in tobacco (Nicotiana tabacum L.). The aim of the present study was to investigate the activity and composition of the root exudates from resistant and susceptible tobacco cultivars. The root exudates of the resistant cultivar Gexin 3 showed inhibitory activity against P. nicotianae, while the exudates of susceptible cultivar Xiaohuangjin 1025 stimulated the colony growth but had no effect on spore germination. Metabolic profiling using liquid chromatography/electrospray ionization-quadrupole-time-of-flight mass spectrometry depicted differing metabolic patterns of root exudates between Gexin 3 and Xiaohuangjin 1025. The activity and composition of root exudates was altered by P. nicotianae inoculation. Multivariate analysis showed that root exudates (including organic acids, alkaloids, fatty acids, and esters) were different between the two varieties. The defense substances in root exudates, such as tartaric acid, ferulic acid, and lauric acid, may represent a pre-infection prevention strategy for tobacco. Phenylpropanoids as well as inducers of salicylic acid, fatty acids, 6-hydroxyhexanoic acid, and hydrojasmonate may be involved in tobacco defense responses. Compared to the susceptible cultivar, the roots of the resistant cultivar exhibited high enzyme activities of phenylalanine ammonia-lyase, cinnamate-4-hydroxylase and 4-coumarate-CoA ligase, which may prompt the synthesis and secretion of phenylpropanoids. Our results indicated that the root exudates not only provide a pre-infection prevention strategy by exuding antimicrobial substances, but also increase tobacco disease resistance by eliciting plant defense responses. In addition, some defense compounds as well as compounds that play a role in inducing plant defense responses, showed potential for disease control application. This study provides an insight into possible disease resistance mechanisms of root exudates, and attempts the beneficial utilization of these secondary metabolites of plants.

Dataset Information

Multiomic Profiling of Tyrosine Kinase Inhibitor-Resistant K562 Cells Suggests Metabolic Reprogramming To Promote Cell Survival.

Publications

Multiomic Profiling of Tyrosine Kinase Inhibitor-Resistant K562 Cells Suggests Metabolic Reprogramming To Promote Cell Survival.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets