Selective inhibitor of proteasome's caspase-like sites sensitizes cells to specific inhibition of chymotrypsin-like sites.
Proteasomes degrade most proteins in mammalian cells and are established targets of anticancer drugs. All eukaryotic proteasomes have three types of active sites: chymotrypsin-like, trypsin-like, and caspase-like. Chymotrypsin-like sites are the most important in protein degradation and are the primary target of most proteasome inhibitors. The biological roles of trypsin-like and caspase-like sites and their potential as cotargets of antineoplastic agents are not well defined. Here we describe the development of site-specific inhibitors and active-site probes of chymotrypsin-like and caspase-like sites. Using these compounds, we show that cytotoxicity of proteasome inhibitors does not correlate with inhibition of chymotrypsin-like sites and that coinhibition of either trypsin-like and/or caspase-like sites is needed to achieve maximal cytotoxicity. Thus, caspase-like and trypsin-like sites must be considered as cotargets of anticancer drugs.
Britton
Matthew
M
Department of Pharmacology and Toxicology, Dartmouth Medical School, 1 Medical Center Drive, HB7936, Lebanon, NH 03756, USA.
Lucas
Marcella M
MM
Downey
Sondra L
SL
Screen
Michael
M
Pletnev
Alexandre A
AA
Verdoes
Martijn
M
Tokhunts
Robert A
RA
Amir
Omar
O
Goddard
Ayrton L
AL
Pelphrey
Philip M
PM
Wright
Dennis L
DL
Overkleeft
Herman S
HS
Kisselev
Alexei F
AF
D000970:Antineoplastic Agents / Q000737:chemistry* / Q000633:toxicity; D020169:Caspases / Q000378:metabolism; D020134:Catalytic Domain; D002460:Cell Line; D002918:Chymotrypsin / Q000378:metabolism; D006801:Humans; D011480:Protease Inhibitors / Q000737:chemistry* / Q000633:toxicity; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D061988:Proteasome Inhibitors; D025801:Ubiquitin / Q000378:metabolism
D000970:Antineoplastic Agents; D011480:Protease Inhibitors; D061988:Proteasome Inhibitors; D025801:Ubiquitin; D002918:Chymotrypsin; D020169:Caspases; D046988:Proteasome Endopeptidase Complex