Dataset Information

Quantitative proteomics explores the potential targets and action mechanisms of hydroxychloroquine

ABSTRACT: Hydroxychloroquine (HCQ) is an autophagy inhibitor that has been used for the treatment of many diseases, such as malaria, rheumatoid arthritis, systemic lupus erythematosus, cancer, and so on. Despite the therapeutic advances in these diseases, the underlying mechanisms have not been well determined and hinder the rational use of this drug in the future. Here, we explored the possible mechanisms and identified the potential binding targets of HCQ by performing quantitative proteomics and thermal proteome profiling on MIA PaCa-2 cells. This study revealed that HCQ may exert its functions by targeting or regulating the expression of some autophagy-related proteins, such as galectin-8 (LGALS8), mitogen-activated protein kinase 8 (MAPK8), Ribosyldihydronicotinamide dehydrogenase (NQO2), Transport protein Sec23A (SEC23A), and so on. Furthermore, HCQ may prevent the progression of pancreatic cancer by regulating the expression of Nesprin-2 (SYNE2), Protein-S-isoprenylcysteine O-methyltransferase (ICMT) and Cotranscriptional regulator FAM172A (FAM172A). Therefore, these findings not only identify potential binding targets for HCQ but also revealed the non-canonical mechanisms of HCQ that may contribute to pancreatic cancer treatment.

INSTRUMENT(S): Q Exactive HF

ORGANISM(S): Homo Sapiens (human)

SUBMITTER: He Huang

LAB HEAD: He Huang

PROVIDER: PXD034196 | Pride | 2022-10-13

REPOSITORIES: Pride

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Publications

Quantitative Proteomics Explore the Potential Targets and Action Mechanisms of Hydroxychloroquine.

Zhao Jingxiang J Zhao Zhiqiang Z Hou Wanting W Jiang Yue Y Liu Guobin G Ren Xuelian X Liu Kun K Liu Hong H Chen Kaixian K Huang He H

Molecules (Basel, Switzerland) 20220814 16

Hydroxychloroquine (HCQ) is an autophagy inhibitor that has been used for the treatment of many diseases, such as malaria, rheumatoid arthritis, systemic lupus erythematosus, and cancer. Despite the therapeutic advances in these diseases, the underlying mechanisms have not been well determined and hinder the rational use of this drug in the future. Here, we explored the possible mechanisms and identified the potential binding targets of HCQ by performing quantitative proteomics and thermal prote ...[more]

PMID: 36014414

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Project description:The molecular mechanisms underlying exceptional radioresistance in pancreatic cancer remain elusive. In the present study, we established a stable radioresistant pancreatic cancer cell line MIA PaCa-2-R by exposing the parental MIA PaCa-2 cells to fractionated ionizing radiation (IR). Systematic proteomics and bioinformatics comparison of protein expression in MIA PaCa-2 and MIA PaCa-2-R cells revealed that several growth factor- and cytokine-mediated pathways, including the OSM/STAT3, PI3K/AKT and MAPK/ERK pathways, were activated in the radioresistant cells, leading to enhanced cell migration, invasion and epithelial-mesenchymal transition (EMT), and inhibition of apoptosis. We focused functional analysis on one of the most upregulated proteins in the radioresistant cells, CD73, which is a cell surface protein that is overexpressed in a variety types of cancer. Ectopic overexpression of CD73 in the parent cells resulted in radioresistance and conferred resistance to IR-induced apoptosis. Knockdown of CD73 resensitized the radioresistant cells to IR and IR-induced apoptosis. The effect of CD73 on radioresistance and apoptosis is independent of the enzymatic activity of CD73. Further studies suggest that CD73 confers acquired radioresistance in pancreatic cancer cells at least in part through inactivating proapoptotic protein BAD via phosphorylation of BAD at Ser-136. Furthermore, we found that knockdown of CD73 in the radioresistant cells alone reverted the gene expression and phenotype of the radioresistant cells from those of mesenchymal-like cells to the ones of epithelial cells, demonstrating that CD73 upregulation is required for maintaining EMT in the radioresistant cells. Our results support the notion that the enhanced growth factor/cytokine signaling that promotes epithelial-mesenchymal plasticity, and acquisition of cancer stem-like cell properties contributes to acquired radioresistance in the residual surviving cells after fractionated irradiation, and that CD73 is a novel downstream factor of those enhanced signaling and acts to confers acquired radioresistance and maintains EMT in the radioresistant pancreatic cancer cells.

Dataset Information

Quantitative proteomics explores the potential targets and action mechanisms of hydroxychloroquine

Publications

Quantitative Proteomics Explore the Potential Targets and Action Mechanisms of Hydroxychloroquine.

Similar Datasets

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