Dynamic proteomics of individual cancer cells in response to a drug.
Why do seemingly identical cells respond differently to a drug? To address this, we studied the dynamics and variability of the protein response of human cancer cells to a chemotherapy drug, camptothecin. We present a dynamic-proteomics approach that measures the levels and locations of nearly 1000 different endogenously tagged proteins in individual living cells at high temporal resolution. All cells show rapid translocation of proteins specific to the drug mechanism, including the drug target (topoisomerase-1), and slower, wide-ranging temporal waves of protein degradation and accumulation. However, the cells differ in the behavior of a subset of proteins. We identify proteins whose dynamics differ widely between cells, in a way that corresponds to the outcomes-cell death or survival. This opens the way to understanding molecular responses to drugs in individual cells.
Cohen
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AA
Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot 76100, Israel. ariel.cohen@weizmann.ac.il
Geva-Zatorsky
N
N
Eden
E
E
Frenkel-Morgenstern
M
M
Issaeva
I
I
Sigal
A
A
Milo
R
R
Cohen-Saidon
C
C
Liron
Y
Y
Kam
Z
Z
Cohen
L
L
Danon
T
T
Perzov
N
N
Alon
U
U
D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D002166:Camptothecin / Q000494:pharmacology*; D016923:Cell Death; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D002466:Cell Nucleolus / Q000187:drug effects / Q000378:metabolism; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D003593:Cytoplasm / Q000187:drug effects / Q000378:metabolism; D053487:DEAD-box RNA Helicases / Q000378:metabolism; D004249:DNA Damage; D004264:DNA Topoisomerases, Type I / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005453:Fluorescence; D006801:Humans; D008164:Luminescent Proteins / Q000378:metabolism; D008175:Lung Neoplasms / Q000378:metabolism* / Q000473:pathology*; D053858:Metabolic Networks and Pathways; D018384:Oxidative Stress; D011506:Proteins / Q000378:metabolism*; D020543:Proteome / Q000378:metabolism*; D040901:Proteomics; D051818:Replication Protein C / Q000378:metabolism; D059004:Topoisomerase I Inhibitors
D000972:Antineoplastic Agents, Phytogenic; D004791:Enzyme Inhibitors; D008164:Luminescent Proteins; D011506:Proteins; D020543:Proteome; C081632:RFC1 protein, human; D059004:Topoisomerase I Inhibitors; C506749:Ddx5 protein, human; D051818:Replication Protein C; D053487:DEAD-box RNA Helicases; D004264:DNA Topoisomerases, Type I; D002166:Camptothecin