The kinase inhibitor PP1 blocks tumorigenesis induced by RET oncogenes.
Oncogenic activation of the RET receptor tyrosine kinase is common in different human cancers. We found that the pyrazolo-pyrimidine PP1 inhibited RET-derived oncoproteins with a half maximal inhibitor concentration of 80 nM. Furthermore, RET/PTC3-transformed cells treated with 5 microM of PP1 lost proliferative autonomy and showed morphological reversion. PP1 prevented the growth of two human papillary thyroid carcinoma cell lines that carry spontaneous RET/PTC1 rearrangements and blocked anchorage-independent growth and tumorigenicity in nude mice of NIH3T3 fibroblasts expressing the RET/PTC3 oncogene. These findings suggest targeting RET oncogenes with PP1 or related compounds as a novel treatment strategy for RET-associated neoplasms.
Carlomagno
Francesca
F
Centro di Endocrinologia ed Oncologia Sperimentale del CNR c/o Dipartimento di Biologia e Patologia Cellulare e Molecolare L. Califano, Facoltà di Medicina e Chirurgia, Università di Napoli Federico II, 80131 Naples, Italy. persfra@tin.it
Vitagliano
Donata
D
Guida
Teresa
T
Napolitano
Maria
M
Vecchio
Giancarlo
G
Fusco
Alfredo
A
Gazit
Aviv
A
Levitzki
Alexander
A
Santoro
Massimo
M
D016475:3T3 Cells / Q000166:cytology / Q000187:drug effects; D000818:Animals; D002471:Cell Transformation, Neoplastic / Q000187:drug effects* / Q000378:metabolism; D029721:Drosophila Proteins; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D015870:Gene Expression; D007987:Gonadotropin-Releasing Hormone / Q000031:analogs & derivatives*; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009857:Oncogenes; D010766:Phosphorylation / Q000187:drug effects; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics* / Q000378:metabolism; D051096:Proto-Oncogene Proteins c-ret; D011720:Pyrazoles / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013964:Thyroid Neoplasms / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics; D014407:Tumor Cells, Cultured
C108123:4-amino-5-(4-methylphenyl)-7-(tert-butyl)pyrazolo(3,4-d)pyrimidine; D029721:Drosophila Proteins; D004791:Enzyme Inhibitors; D011518:Proto-Oncogene Proteins; D011720:Pyrazoles; D011743:Pyrimidines; D007987:Gonadotropin-Releasing Hormone; C040278:MI 1544; D051096:Proto-Oncogene Proteins c-ret; D020794:Receptor Protein-Tyrosine Kinases; C416649:Ret protein, Drosophila; C494999:Ret protein, mouse