A chemical and phosphoproteomic characterization of dasatinib action in lung cancer

Li, Jiannong; Rix, Uwe; Fang, Bin; Bai, Yun; Edwards, A.; Colinge, Jacques; Bennett, Keiryn L.; Gao, Jingchun; Song, Lanxi; Eschrich, Steven; Superti‐Furga, Giulio; Koomen, John M.; Haura, Eric B.

doi:10.1038/nchembio.332

Cited by 248 publications

(291 citation statements)

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“…The potential of dasatinib in adenomas has not been investigated yet. We show a growth reduction in colon adenoma cells at relatively low concentrations of dasatinib, indicating that the observed effects are Src specific (Li et al, 2010). Our experiments are a proof-of-concept, showing that pathway analysis results in the identification of pathways related to carcinogenesis, which can finally lead to effective targeting of those pathways.…”

Section: Discussionsupporting

confidence: 55%

A bioinformatical and functional approach to identify novel strategies for chemoprevention of colorectal cancer

et al. 2011

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Section: Discussionsupporting

confidence: 55%

A bioinformatical and functional approach to identify novel strategies for chemoprevention of colorectal cancer

et al. 2011

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“…On the other hand, dasatinib has anticancer effects not only on CML but also on BCR/ABL negative tumors including chronic lymphoid leukemia, acute myeloid leukemia, prostate, lung, and non-small lung cancers [47][48][49][50]. In addition to inhibition of BCR/ABL, dasatinib can also target SRC family kinases, Lyn kinase, and EGFR [47][48][49][50].…”

Section: Discussionmentioning

confidence: 99%

“…In addition to inhibition of BCR/ABL, dasatinib can also target SRC family kinases, Lyn kinase, and EGFR [47][48][49][50]. In order to understand the mechanisms of dasatinib-induced apoptosis, we examined the expression patterns of ceramide-metabolizing genes in CML cells exposed to dasatinib.…”

Section: Discussionmentioning

confidence: 99%

A novel mechanism of dasatinib-induced apoptosis in chronic myeloid leukemia; ceramide synthase and ceramide clearance genes

et al. 2011

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Sphingolipids are bioeffector molecules that control various aspects of cell growth, proliferation, apoptosis, and drug resistance. Ceramides, the central molecule of sphingolipid metabolism, are inducer of apoptosis and inhibitors of proliferation. Sphingosine-1-phosphate (S1P) and glucosyleceramide, converted from ceramides by sphingosine kinase-1 (SK-1) and glucosyleceramide synthase (GCS) enzymes, respectively, inhibit apoptosis and develop resistance to chemotherapeutic drugs. In this study, we examined the therapeutic potentials of bioactive sphingolipids in chronic myeloid leukemia (CML) alone and in combination with dasatinib in addition to investigate the roles of ceramide-metabolizing genes in dasatinib-induced apoptosis. Cytotoxic effects of dasatinib, C8:ceramide, PDMP, and SK-1 inhibitor were determined by XTT cell proliferation assay. Changes in caspase-3 enzyme activity and mitochondrial membrane potential (MMP) were measured using caspase-3 colorimetric assay and JC-1 MMP detection kit. Expression levels of ceramide-metabolizing genes were examined by qRT-PCR. Application of ceramide analogs and inhibitors of ceramide clearance genes decreased cell proliferation and induced apoptosis. Targeting bioactive sphingolipids towards generation/accumulation of ceramides increased apoptotic effects of dasatinib, synergistically. It was shown for the first time that dasatinib induces apoptosis through downregulating expression levels of antiapoptotic SK-1 but not GCS, and upregulating expression levels of ceramide synthase (CerS) genes, especially CerS1, in K562 cells. On the other hand, dasatinib downregulates expression levels of both GCS and SK-1 and upregulate apoptotic CerS2, −5 and −6 genes in Meg-01 cells. Increasing endogenous ceramide levels and decreasing prosurvival lipids, S1P, and GC, can open the way of more effective treatment of CML.

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“…Understanding this could have an enormous impact in many aspects of drug development and public health. 1 Ideally, one would have dedicated (phospho)proteomic and chemoproteomic experiments, 2 where the binding targets of the drug of interest are identified, and the amount and post-translational modifications of many proteins are measured upon perturbation with the drug. However, phospho-and chemo-proteomic data are still relatively hard to generate and hence very few datasets exist.…”

Section: Introductionmentioning

confidence: 99%

Identification of drug-specific pathways based on gene expression data: application to drug induced lung injury

et al. 2015

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Identification of signaling pathways that are functional in a specific biological context is a major challenge in systems biology, and could be instrumental to the study of complex diseases and various aspects of drug discovery. Recent approaches have attempted to combine gene expression data with prior knowledge of protein connectivity in the form of a PPI network, and employ computational methods to identify subsets of the protein-protein-interaction (PPI) network that are functional, based on the data at hand. However, the use of undirected networks limits the mechanistic insight that can be drawn, since it does not allow for following mechanistically signal transduction from one node to the next. To address this important issue, we used a directed, signaling network as a scaffold to represent protein connectivity, and implemented an Integer Linear Programming (ILP) formulation to model the rules of signal transduction from one node to the next in the network. We then optimized the structure of the network to best fit the gene expression data at hand. We illustrated the utility of ILP modeling with a case study of drug induced lung injury. We identified the modes of action of 200 lung toxic drugs based on their gene expression profiles and, subsequently, merged the drug specific pathways to construct a signaling network that captured the mechanisms underlying Drug Induced Lung Disease (DILD). We further demonstrated the predictive power and biological relevance of the DILD network by applying it to identify drugs with relevant pharmacological mechanisms for treating lung injury. Insight, innovation, integrationIn this manuscript we introduce a novel approach for the identification of signaling pathways that are functional in a specific biological context, by leveraging gene expression data and prior knowledge of protein connectivity. In more detail, we introduce a linear programming formulation to model signal transduction from one node to the next in a Prior Knowledge Network (PKN), and by minimizing the mismatch between model predictions and experimental data, we are able to identify subsets of the PKN that are most probably functional in the specific biological context. More specifically, we address the problem of identifying the modes of action of drugs that have been reported to induce respiratory side effects, based on their gene expression profiles, and subsequently, merge the drug specific pathways together to construct a signaling network that captures the signaling mechanisms underlying Drug Induced Lung Disease (DILD). Moreover, to demonstrate the predictive power and biological relevance of the DILD network, we use it to suggest potential drug repositioning for treating lung injury.

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A chemical and phosphoproteomic characterization of dasatinib action in lung cancer

Cited by 248 publications

References 50 publications

A bioinformatical and functional approach to identify novel strategies for chemoprevention of colorectal cancer

A bioinformatical and functional approach to identify novel strategies for chemoprevention of colorectal cancer

A novel mechanism of dasatinib-induced apoptosis in chronic myeloid leukemia; ceramide synthase and ceramide clearance genes

Identification of drug-specific pathways based on gene expression data: application to drug induced lung injury

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