Inactivation of Ret/Ptc1 oncoprotein and inhibition of papillary thyroid
carcinoma cell proliferation by indolinone RPI-1 |
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Authors: | Email author" target="_blank">C?LanziEmail author G?Cassinelli G?Cuccuru N?Zaffaroni R?Supino S?Vignati C?Zanchi M?Yamamoto F?Zunino |
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Institution: | (1) Preclinical Chemotherapy and Pharmacology Unit, Istituto Nazionale Tumori, via G. Venezian 1, 20133 Milan, Italy;(2) Department of Experimental Oncology, Istituto Nazionale Tumori, via G. Venezian 1, 20133 Milan, Italy;(3) Department of Neurology, Nagoya University School of Medicine, 466 Nagoya, Japan |
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Abstract: | Genetic alterations causing oncogenic activation of the RET gene are recognized as pathogenic
events in papillary and medullary thyroid carcinomas. Inhibition of Ret oncoprotein functions could
thereby represent a specific therapeutic approach. We previously described the inhibitory activity
of the 2-indolinone derivative RPI-1 (formerly Cpd1) on the tyrosine kinase activity and transforming
ability of the products of the RET/PTC1 oncogene exogenously expressed in murine cells. In the
present study, we investigated the effects of RPI-1 in the human papillary thyroid carcinoma cell
line TPC-1 spontaneously harboring the RET/PTC1 rearrangement. Treatment with RPI-1 inhibited cell
proliferation and induced accumulation of cells at the G2 cell cycle phase. In treated cells,
Ret/Ptc1 tyrosine phosphorylation was abolished along with its binding to Shc and phospholipase
C, thereby indicating abrogation of constitutive signaling mediated by the oncoprotein. Activation
of JNK2 and AKT was abolished, thus supporting the drug inhibitory efficacy on downstream pathways.
In addition, cell growth inhibition was associated with a reduction in telomerase activity by nearly
85%. These findings in a cellular context relevant to the pathological function of RET oncogenes
support the role of Ret oncoproteins as useful targets for therapeutic intervention, and suggest
RPI-1 as a promising candidate for preclinical development in the treatment of thyroid tumors
expressing RET oncogenes.Received 31 December 2002; received after revision 21 February 2003; accepted 10 April 2003 |
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Keywords: | Receptor tyrosine kinase Ret oncoprotein thyroid neoplasms c-Jun N-terminal kinase AKT telomerase 2-indolinone |
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