Investigation of cancer drug resistance mechanisms by phosphoproteomics

Boulos, Joelle C.; Idres, Muhammad Rahama Yousof; Efferth, Thomas

doi:10.1016/j.phrs.2020.105091

Cited by 22 publications

(16 citation statements)

References 114 publications

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“…It is, therefore, important to investigate an anticancer effect of LAT1 inhibitors on a system‐wide scale. Recent deep phosphoproteomics arose as advanced tools for the study of cancer therapies using tyrosine kinase inhibitors 47 . A more recent study showed that phosphoproteomics integrated with global proteomics revealed key networks of cancer cell resistance to cisplatin, 48 which shows usefulness of integrative proteomics and phosphoproteomics for the study of anticancer drugs other than kinase inhibitors.…”

Section: Introductionmentioning

confidence: 99%

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Proteomics and phosphoproteomics reveal key regulators associated with cytostatic effect of amino acid transporter LAT1 inhibitor

et al. 2020

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L‐type amino acid transporter 1 (LAT1) is highly expressed in various cancers and plays important roles not only in the amino acid uptake necessary for cancer growth but also in cellular signaling. Recent research studies have reported anticancer effects of LAT1 inhibitors and demonstrated their potential for cancer therapy. Here, we characterized the proteome and phosphoproteome in LAT1‐inhibited cancer cells. We used JPH203, a selective LAT1 inhibitor, and performed tandem mass tag–based quantitative proteomics and phosphoproteomics on four biliary tract cancer cell lines sensitive to JPH203. Our analysis identified hundreds to thousands of differentially expressed proteins and phosphorylated sites, demonstrating the broad influence of LAT1 inhibition. Our findings showed various functional pathways altered by LAT1 inhibition, and provided possible regulators and key kinases in LAT1‐inhibited cells. Comparison of these changes among cell lines provides insights into general pathways and regulators associated with LAT1 inhibition and particularly suggests the importance of cell cycle–related pathways and kinases. Moreover, we evaluated the anticancer effects of the combinations of JPH203 with cell cycle–related kinase inhibitors and demonstrated their potential for cancer therapy. This is the first study providing the proteome‐wide scope of both protein expression and phosphorylation signaling perturbed by LAT1 inhibition in cancer cells.

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Section: Introductionmentioning

confidence: 99%

“…Recent deep phosphoproteomics arose as advanced tools for the study of cancer therapies using tyrosine kinase inhibitors. 47 A more recent study showed that phosphoproteomics integrated with global proteomics revealed key networks of cancer cell resistance to cisplatin, 48…”

Section: Introductionmentioning

confidence: 99%

Proteomics and phosphoproteomics reveal key regulators associated with cytostatic effect of amino acid transporter LAT1 inhibitor

et al. 2020

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“…This result validated the results we observed with the NCI tumor line panel. Multidrug-resistant CEM/ADR5000 cells overexpressed the ABC-transporter P-glycoprotein, known to expel a large variety of chemically and functionally diverse anticancer drugs out of tumor cells, which ultimately can lead to the failure of chemotherapy in the clinical setting [20]. Our data suggested that P-glycoprotein also recognized crizotinib as substrate and that crizotinib is part of the multidrug resistance phenotype.…”

Section: Discussionmentioning

confidence: 69%

Repurposing of the ALK Inhibitor Crizotinib for Acute Leukemia and Multiple Myeloma Cells

et al. 2021

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Crizotinib was a first generation of ALK tyrosine kinase inhibitor approved for the treatment of ALK-positive non-small-cell lung carcinoma (NSCLC) patients. COMPARE and cluster analyses of transcriptomic data of the NCI cell line panel indicated that genes with different cellular functions regulated the sensitivity or resistance of cancer cells to crizotinib. Transcription factor binding motif analyses in gene promoters divulged two transcription factors possibly regulating the expression of these genes, i.e., RXRA and GATA1, which are important for leukemia and erythroid development, respectively. COMPARE analyses also implied that cell lines of various cancer types displayed varying degrees of sensitivity to crizotinib. Unexpectedly, leukemia but not lung cancer cells were the most sensitive cells among the different types of NCI cancer cell lines. Re-examining this result in another panel of cell lines indeed revealed that crizotinib exhibited potent cytotoxicity towards acute myeloid leukemia and multiple myeloma cells. P-glycoprotein-overexpressing CEM/ADR5000 leukemia cells were cross-resistant to crizotinib. NCI-H929 multiple myeloma cells were the most sensitive cells. Hence, we evaluated the mode of action of crizotinib on these cells. Although crizotinib is a TKI, it showed highest correlation rates with DNA topoisomerase II inhibitors and tubulin inhibitors. The altered gene expression profiles after crizotinib treatment predicted several networks, where TOP2A and genes related to cell cycle were downregulated. Cell cycle analyses showed that cells incubated with crizotinib for 24 h accumulated in the G2M phase. Crizotinib also increased the number of p-H3(Ser10)-positive NCI-H929 cells illustrating crizotinib’s ability to prevent mitotic exit. However, cells accumulated in the sub-G0G1 fraction with longer incubation periods, indicating apoptosis induction. Additionally, crizotinib disassembled the tubulin network of U2OS cells expressing an α-tubulin-GFP fusion protein, preventing migration of cancer cells. This result was verified by in vitro tubulin polymerization assays. In silico molecular docking also revealed a strong binding affinity of crizotinib to the colchicine and Vinca alkaloid binding sites. Taken together, these results demonstrate that crizotinib destabilized microtubules. Additionally, the decatenation assay showed that crizotinib partwise inhibited the catalytic activity of DNA topoisomerase II. In conclusion, crizotinib exerted kinase-independent cytotoxic effects through the dual inhibition of tubulin polymerization and topoisomerase II and might be used to treat not only NSCLC but also multiple myeloma.

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“…The main reasons of chemotherapy failure are drug resistance development in tumor cells and the high susceptibility of normal tissues to treatment-related toxicity [ 6 , 7 , 8 , 9 , 10 ]. Some important multidrug resistance mechanisms in cancer are apoptosis inhibition, DNA repair, drug efflux, and altered drug metabolism [ 5 , 11 , 12 , 13 , 14 , 15 ]. Vesicle trafficking, including the release of extracellular micro-vesicles, is critical in carcinogenesis and progression, which involves invasion, metastasis, cell cycle regulation, angiogenesis, tumor immune privilege, and chromosomal aberrations, all of which contribute to the development of multidrug resistance (MDR) [ 16 ].…”

Section: Introductionmentioning

confidence: 99%

Identification of Novel Anthracycline Resistance Genes and Their Inhibitors

et al. 2021

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Differentially expressed genes have been previously identified by us in multidrug-resistant tumor cells mainly resistant to doxorubicin. In the present study, we exemplarily focused on some of these genes to investigate their causative relationship with drug resistance. HMOX1, NEIL2, and PRKCA were overexpressed by lentiviral-plasmid-based transfection of HEK293 cells. An in silico drug repurposing approach was applied using virtual screening and molecular docking of FDA-approved drugs to identify inhibitors of these new drug-resistant genes. Overexpression of the selected genes conferred resistance to doxorubicin and daunorubicin but not to vincristine, docetaxel, and cisplatin, indicating the involvement of these genes in resistance to anthracyclines but not to a broader MDR phenotype. Using virtual drug screening and molecular docking analyses, we identified FDA-approved compounds (conivaptan, bexarotene, and desloratadine) that were interacting with HMOX1 and PRKCA at even stronger binding affinities than 1-(adamantan-1-yl)-2-(1H-imidazol-1-yl)ethenone and ellagic acid as known inhibitors of HMOX1 and PRKCA, respectively. Conivaptan treatment increased doxorubicin sensitivity of both HMOX1- and PRKCA-transfected cell lines. Bexarotene treatment had a comparable doxorubicin-sensitizing effect in HMOX1-transfected cells and desloratadine in PRKCA-transfected cells. Novel drug resistance mechanisms independent of ABC transporters have been identified that contribute to anthracycline resistance in MDR cells.

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Investigation of cancer drug resistance mechanisms by phosphoproteomics

Cited by 22 publications

References 114 publications

Proteomics and phosphoproteomics reveal key regulators associated with cytostatic effect of amino acid transporter LAT1 inhibitor

Proteomics and phosphoproteomics reveal key regulators associated with cytostatic effect of amino acid transporter LAT1 inhibitor

Repurposing of the ALK Inhibitor Crizotinib for Acute Leukemia and Multiple Myeloma Cells

Identification of Novel Anthracycline Resistance Genes and Their Inhibitors

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