The antitumor somatostatin analogue TT-232 induces cell cycle arrest through PKCdelta and c-Src.
The heptapeptide TT-232 is structurally related to the hypothalamic hormone somatostatin and shows promise as an anticancer drug because of its tumor-specific cytotoxic effects. Apart from the ability to induce apoptosis, the synthetic peptide can trigger an alternative pathway that leads to cell cycle arrest in certain tumor cell systems. We found that pulse treatment with TT-232 blocks the cell cycle G(1)/S transition irreversibly in A431 cells. Investigation of the TT-232 signaling pathway yielded results similar to those reported for somatostatin although its affinity to the somatostatin receptor 1 is significantly reduced. We show that functional protein kinase C (PKC) delta as well as c-Src are necessary mediators of the TT-232 cytostatic effect and we propose a signaling pathway that leads to cell cycle arrest.
Steták
A
A
Peptide Chemistry Research Group, Semmelweis University, Budapest, H-1088 Hungary. stetak@hotmail.com
Lankenau
A
A
Vántus
T
T
Csermely
P
P
Ullrich
A
A
Kéri
G
G
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D019556:COS Cells; D000081247:CSK Tyrosine-Protein Kinase; D002453:Cell Cycle / Q000187:drug effects* / Q000502:physiology; D002462:Cell Membrane / Q000502:physiology; D002522:Chlorocebus aethiops; D004790:Enzyme Induction; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005419:Flavonoids / Q000494:pharmacology; D016193:G1 Phase; D016391:Genes, src; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D007527:Isoenzymes / Q000096:biosynthesis / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology; D008301:Maleimides / Q000494:pharmacology; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D010456:Peptides, Cyclic / Q000494:pharmacology*; D011493:Protein Kinase C / Q000096:biosynthesis / Q000378:metabolism*; D051745:Protein Kinase C-delta; D021381:Protein Transport; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D017481:Receptors, Somatostatin / Q000187:drug effects / Q000502:physiology; D016196:S Phase; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013004:Somatostatin / Q000031:analogs & derivatives; D014407:Tumor Cells, Cultured; D010566:Virulence Factors, Bordetella / Q000494:pharmacology; D019061:src-Family Kinases
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D005419:Flavonoids; D007211:Indoles; D007527:Isoenzymes; D008301:Maleimides; D010456:Peptides, Cyclic; D017481:Receptors, Somatostatin; D010566:Virulence Factors, Bordetella; C101130:somatostatin receptor type 1; C094462:TT2-32; D013004:Somatostatin; D011505:Protein-Tyrosine Kinases; D000081247:CSK Tyrosine-Protein Kinase; D019061:src-Family Kinases; C000631346:CSK protein, human; C497258:PRKCD protein, human; D011493:Protein Kinase C; D051745:Protein Kinase C-delta; D020928:Mitogen-Activated Protein Kinases; C070515:bisindolylmaleimide I; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one