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 cells, where a 4-h preincubation with the peptide irreversibly induced a cell death program, which involves DNA-laddering and the appearance of shrunken nuclei, but is unrelated to somatostatin signalling. Early intracellular signals of TT-232 include a transient two-fold activation of the extracellular signal-regulated kinase (ERK2) and a strong and sustained activation of the stress-activated protein kinases c-Jun NH(2)-terminal kinase (JNK)/SAPK and p38MAPK. Blocking the signalling to ERK or p38MAPK activation had no effect on the TT-232-induced cell killing. At the commitment time for inducing cell death, TT-232 decreased EGFR-tyrosine phosphorylation and prevented epidermial growth factor (EGF)-induced events like cRaf-1 and ERK2 activation. Signalling to ERK activation by FCS, phorbol 12-myristate 13-acetate (PMA) and platelet-derived growth factor (PDGF) was similarly blocked. Our data 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.
Vántus
T
T
Peptide Biochemistry Research Group, Department of Medical Biochemistry, Budapest H-1088, Hungary.
Kéri
G
G
Krivickiene
Z
Z
Valius
M
M
Steták
A
A
Keppens
S
S
Csermely
P
P
Bauer
P I
PI
Bökönyi
G
G
Declercq
W
W
Vandenabeele
P
P
Merlevede
W
W
Vandenheede
J R
JR
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D004336:Drug Antagonism; D004815:Epidermal Growth Factor / Q000494:pharmacology; D006801:Humans; D007700:Kinetics; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048055:Mitogen-Activated Protein Kinase 8; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D009369:Neoplasms / Q000201:enzymology / Q000473:pathology; D010456:Peptides, Cyclic / Q000494:pharmacology*; D013004:Somatostatin / Q000494:pharmacology / Q000031:analogs & derivatives; D014407:Tumor Cells, Cultured; D048051:p38 Mitogen-Activated Protein Kinases
D000970:Antineoplastic Agents; D010456:Peptides, Cyclic; C094462:TT2-32; D013004:Somatostatin; D004815:Epidermal Growth Factor; D019950:Mitogen-Activated Protein Kinase 1; D048055:Mitogen-Activated Protein Kinase 8; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases