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Comparative proteomics of dying and surviving cancer cells improves the identification of drug targets and sheds light on cell life/death decisions.

Comparative proteomics of dying and surviving cancer cells improves the identification of drug targets and sheds light on cell life/death decisions.
Author Information (click to view)

Saei AA, Sabatier P, Güler Tokat Ü, Chernobrovkin A, Pirmoradian M, Zubarev RA,


Saei AA, Sabatier P, Güler Tokat Ü, Chernobrovkin A, Pirmoradian M, Zubarev RA, (click to view)

Saei AA, Sabatier P, Güler Tokat Ü, Chernobrovkin A, Pirmoradian M, Zubarev RA,

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Molecular & cellular proteomics : MCP 2018 03 23() pii 10.1074/mcp.RA118.000610

Abstract

Chemotherapeutics cause the detachment and death of adherent cancer cells. When studying the proteome changes to determine the protein target and mechanism of action of anticancer drugs, the still-attached cells are normally used, while the detached cells are usually ignored. To test the hypothesis that proteomes of detached cells contain valuable information, we separately analyzed the proteomes of detached and attached HCT-116, A375 and RKO cells treated for 48 h with 5-fluorouracil, methotrexate and paclitaxel. Individually, the proteomic data on attached and detached cells had comparable performance in target and drug mechanism deconvolution, while the combined data significantly improved the target ranking for paclitaxel. Comparative analysis of attached vs. detached proteomes provided further insight into cell life and death decision making. Six proteins consistently up- or down-regulated in the detached vs attached cells regardless of the drug and cell type were discovered; their role in cell death/survival was tested by silencing them with siRNA. Knocking down USP11, CTTN, ACAA2 and EIF4H had anti-proliferative effects, affecting UHRF1 additionally sensitized the cells to the anticancer drugs, while knocking down RNF-40 increased cell survival against the treatments. Therefore, adding detached cells to the expression proteomics analysis of drug-treated cells can significantly increase the analytical value of the approach. The data have been deposited to the ProteomeXchange with identifier PXD007686.

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