Quantitative profiling of caspase-cleaved substrates reveals different drug-induced and cell-type patterns in apoptosis.
Proapoptotic drugs are a mainstay of cancer drug treatment. These drugs stress cells and ultimately trigger the activation of caspases, cysteine-class proteases that cleave after aspartic acid and deconstruct the cell. It is well known that cells respond differently to proapoptotic cancer drug treatments. Here, using a global and unbiased quantitative N-terminomics technology, we show that ~500 products of caspase cleavage and their kinetics vary dramatically between cell type and cytotoxic drug treatment. It is likely that variations arise from differences in baseline proteome composition of the cell type and the alterations induced by drug treatments to yield a unique cohort of proteins that caspases finally target. Many targets are specific to both drug treatment and cell type, providing candidate-specific biomarkers for apoptosis. For example, in multiple myeloma cells treated with the proteasome inhibitor bortezomib, levels of activating transcription factor-4 increase dramatically early in drug treatment and then decrease upon cleavage by activated caspases. Thus, caspase-derived cleavage products are a sensitive reflection of cell-type and drug-induced stress, and provide useful fingerprints for mechanisms of drug action and response.
Department of Pharmaceutical Chemistry, University of California, San Francisco, CA 94114, USA.
Kazutaka
K
Shimbo
Gerald W
GW
Hsu
Huy
H
Nguyen
Sami
S
Mahrus
Jonathan C
JC
Trinidad
Alma L
AL
Burlingame
James A
JA
Wells
D051701:Activating Transcription Factor 4 / Q000378:metabolism; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D014408:Biomarkers, Tumor / Q000378:metabolism*; D001897:Boronic Acids / Q000494:pharmacology; D000069286:Bortezomib; D020169:Caspases / Q000378:metabolism*; D003603:Cytotoxins / Q000737:chemistry / Q000494:pharmacology*; D004354:Drug Screening Assays, Antitumor / Q000379:methods; D006801:Humans; D019169:Jurkat Cells; D007700:Kinetics; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000201:enzymology; D009363:Neoplasm Proteins / Q000378:metabolism*; D020543:Proteome / Q000378:metabolism; D011719:Pyrazines / Q000494:pharmacology
C497109:ATF4 protein, human; D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D001897:Boronic Acids; D003603:Cytotoxins; D009363:Neoplasm Proteins; D020543:Proteome; D011719:Pyrazines; D051701:Activating Transcription Factor 4; D000069286:Bortezomib; D020169:Caspases