DIA-Based Proteomics Identifies IDH2 as a Targetable Regulator of Acquired Drug Resistance in Chronic Myeloid Leukemia

Autor: Wei Liu, Yaoting Sun, Weigang Ge, Fangfei Zhang, Lin Gan, Yi Zhu, Tiannan Guo, Kexin Liu
Jazyk: angličtina
Rok vydání: 2021
Předmět:
RT
retention time
Proteomics
adriamycin
FDR
false discovery rate
Chronic Myeloid Leukemia
DIA
data-independent acquisition
PCT
pressure cycling technology
Biochemistry
TKI
tyrosine kinase inhibitor
Analytical Chemistry
CiRT
common index retention time standards
CML
chronic myeloid leukemia
GLS
glutaminase
Leukemia
Myelogenous
Chronic
BCR-ABL Positive
DIA
Humans
Molecular Biology
α-KG
α-ketoglutarate
FA
formic acid
drug resistance
Research
ADR
adriamycin
CV
coefficient of variation
IPA
ingenuity pathway analysis
IDH2
isocitrate dehydrogenase (NADP(+)) 2
TOMM
translocase of the outer mitochondrial membrane
imatinib
MS
mass spectrometry
Doxorubicin
Drug Resistance
Neoplasm
VDAC
voltage-dependent anion channel
DDA
data-dependent acquisition
Imatinib Mesylate
IDH2
K562 Cells
IMA
imatinib mesylate
Zdroj: Molecular & Cellular Proteomics : MCP
ISSN: 1535-9484
1535-9476
Popis: Drug resistance is a critical obstacle to effective treatment in patients with chronic myeloid leukemia. To understand the underlying resistance mechanisms in response to imatinib mesylate (IMA) and adriamycin (ADR), the parental K562 cells were treated with low doses of IMA or ADR for 2 months to generate derivative cells with mild, intermediate, and severe resistance to the drugs as defined by their increasing resistance index. PulseDIA-based (DIA [data-independent acquisition]) quantitative proteomics was then employed to reveal the proteome changes in these resistant cells. In total, 7082 proteins from 98,232 peptides were identified and quantified from the dataset using four DIA software tools including OpenSWATH, Spectronaut, DIA-NN, and EncyclopeDIA. Sirtuin signaling pathway was found to be significantly enriched in both ADR-resistant and IMA-resistant K562 cells. In particular, isocitrate dehydrogenase (NADP(+)) 2 was identified as a potential drug target correlated with the drug resistance phenotype, and its inhibition by the antagonist AGI-6780 reversed the acquired resistance in K562 cells to either ADR or IMA. Together, our study has implicated isocitrate dehydrogenase (NADP(+)) 2 as a potential target that can be therapeutically leveraged to alleviate the drug resistance in K562 cells when treated with IMA and ADR.
Graphical Abstract
Highlights • Temporal proteomic dynamics in the imatinib or adriamycin-induced drug resistance. • Comparison of four DIA software tools (OpenSWATH, Spectronaut, DIA-NN, and EncyclopeDIA). • Sirtuin signaling pathway was significantly regulated in resistant K562 cells. • IDH2 was identified as a potential drug target correlated for resistant K562 cells.
In Brief To understand the underlying resistance mechanisms in response to imatinib (IMA) and adriamycin (ADR), we explored two unique drug resistance models of K562 cells. We applied an optimized DIA–MS method to quantify 98,232 peptides from 7082 proteotypic proteins from these samples using four DIA software tools including OpenSWATH, Spectronaut, DIA-NN, and EncyclopeDIA. The sirtuin signaling pathway was found significantly regulated in both models, and IDH2 was identified as a druggable regulator of acquired drug resistance.
Databáze: OpenAIRE
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