Notch versus the proteasome: what is the target of gamma-secretase inhibitor-I?
gamma-Secretase inhibitors are new anti-cancer agents targeting Notch signaling. Their specificity for Notch is as yet unclear. Han and colleagues investigated the effects of Z-LeuLeuNleu-CHO on growth of breast cancer cells. The results demonstrated a reduction in cell viability primarily via proteasome inhibition independent of Notch activity. Currently, gamma-secretase inhibitors in clinical trials are structurally distinct from Z-LeuLeuNleu-CHO. Their effects on the proteasome are yet to be determined. However, findings from Han and colleagues pose two critical questions: Is the level of proteasomal activity in breast tumors the driving force for growth? What does the Notch pathway contribute to this growth?
Anthony G
AG
Clementz
Clodia
C
Osipo
D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000201:enzymology*; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D007976:Leupeptins / Q000494:pharmacology; D009842:Oligopeptides / Q000494:pharmacology; D051880:Receptors, Notch / Q000037:antagonists & inhibitors*
D007976:Leupeptins; D009842:Oligopeptides; D051880:Receptors, Notch; C523462:benzyloxycarbonyl-leucyl-leucyl-norleucinal; D053829:Amyloid Precursor Protein Secretases; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde