The somatostatin analogue TT-232 induces apoptosis in A431 cells - Sustained activation of stress-activated kinases and inhibition of signalling to extracellular signal-regulated kinases

TT-232 is a somatostatin analogue containing a five-residue ring structure. The present report describes TT-232-induced signalling events in A431 cell s, where a 4-h preincubation with the peptide irreversibly induced a cell d eath program, which involves DNA-laddering and the appearance of shrunken n uclei, but is unrelated to somatostatin signalling. Early intracellular sig nals of TT-232 include a transient two-fold activation of the extracellular signal-regulated kinase (ERK2) and a strong and sustained activation of th e stress-activated protein kinases c-Jun NF12-terminal kinase (JNK)/SAPK an d p38MAPK. Blocking the signalling to ERK or p38MAPK activation had no effe ct on the TTL 232-induced cell killing. At the commitment time for inducing cell death, TT-232 decreased EGFR-tyrosine phosphorylation and prevented e pidermial growth factor (EGF)-induced events like cRaf-1 and ERK2 activatio n. Signalling to ERK activation by FCS, phorbol 12-myristate 13-acetate (PM A) and platelet-derived growth factor (PDGF) was similarly blocked. Our dat a suggest that TT-232 triggers an apoptotic type of cell death, concomitant with a strong activation of JNK and a blockade of cellular ERK2 activation pathways. (C) 2001 Elsevier Science Inc. All rights reserved.