Selective repression of RET proto-oncogene in medullary thyroid carcinoma by a natural alkaloid berberine

Persistent Link:
http://hdl.handle.net/10150/610272
Title:
Selective repression of RET proto-oncogene in medullary thyroid carcinoma by a natural alkaloid berberine
Author:
Kumarasamy, Vishnu M.; Shin, Yoon-Joo; White, John; Sun, Daekyu
Affiliation:
College of Pharmacy, University of Arizona; BIO5 Institute; Arizona Cancer Center
Issue Date:
2015
Publisher:
BioMed Central Ltd
Citation:
Kumarasamy et al. BMC Cancer (2015) 15:599 DOI 10.1186/s12885-015-1610-5
Journal:
BMC Cancer
Rights:
© 2015 Kumarasamy et al. Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/)
Collection Information:
This item is part of the UA Faculty Publications collection. For more information this item or other items in the UA Campus Repository, contact the University of Arizona Libraries at repository@u.library.arizona.edu.
Abstract:
BACKGROUND: The gain-of-function mutation of the RET proto-oncogene, which encodes a receptor tyrosine kinase, is strongly associated with the development of several medullary thyroid carcinomas (MTCs). Thus, the RET protein has been explored as an excellent target for progressive and advanced MTC. In this study we have demonstrated a therapeutic strategy for MTC by suppressing the transcription of RET proto-oncogene though the stabilization of G-quadruplex structure formed on the promoter region of this gene using a natural product berberine. METHODS: Medullary thyroid carcinoma (MTC) TT cell line has been used to evaluate the effects of berberine on RET expression and its downstream signaling pathways. The specificity of berberine was demonstrated by using the papillary thyroid carcinoma TPC1 cell line, which lacks the G-quadruplex forming sequence on the RET promoter region due to chromosomal rearrangement. RESULTS: Berberine suppressed the RET expression by more than 90 % in MTC TT cells at a concentration of 2.5 μg/ml with minimal effect on the TPC1 cells. Canadine, which is a structural analogue of berberine, showed little interaction with RET G-quadruplex and also had no effect on RET expression in MTC TT cells. The down-regulation of RET with berberine further inhibited the cell proliferation through cell cycle arrest and activation of apoptosis in TT cells, which was confirmed by a 2-fold increase in the caspase-3 activity and the down-regulation of cell-cycle regulatory proteins. CONCLUSION: Our data strongly suggest that the G-quadruplex forming region and the stabilization of this structure play a critical role in mediating the repressive effect of berberine on RET transcription.
EISSN:
1471-2407
DOI:
10.1186/s12885-015-1610-5
Version:
Final published version
Additional Links:
http://www.biomedcentral.com/1471-2407/15/599

Full metadata record

DC FieldValue Language
dc.contributor.authorKumarasamy, Vishnu M.en
dc.contributor.authorShin, Yoon-Jooen
dc.contributor.authorWhite, Johnen
dc.contributor.authorSun, Daekyuen
dc.date.accessioned2016-05-20T09:02:48Z-
dc.date.available2016-05-20T09:02:48Z-
dc.date.issued2015en
dc.identifier.citationKumarasamy et al. BMC Cancer (2015) 15:599 DOI 10.1186/s12885-015-1610-5en
dc.identifier.doi10.1186/s12885-015-1610-5en
dc.identifier.urihttp://hdl.handle.net/10150/610272-
dc.description.abstractBACKGROUND: The gain-of-function mutation of the RET proto-oncogene, which encodes a receptor tyrosine kinase, is strongly associated with the development of several medullary thyroid carcinomas (MTCs). Thus, the RET protein has been explored as an excellent target for progressive and advanced MTC. In this study we have demonstrated a therapeutic strategy for MTC by suppressing the transcription of RET proto-oncogene though the stabilization of G-quadruplex structure formed on the promoter region of this gene using a natural product berberine. METHODS: Medullary thyroid carcinoma (MTC) TT cell line has been used to evaluate the effects of berberine on RET expression and its downstream signaling pathways. The specificity of berberine was demonstrated by using the papillary thyroid carcinoma TPC1 cell line, which lacks the G-quadruplex forming sequence on the RET promoter region due to chromosomal rearrangement. RESULTS: Berberine suppressed the RET expression by more than 90 % in MTC TT cells at a concentration of 2.5 μg/ml with minimal effect on the TPC1 cells. Canadine, which is a structural analogue of berberine, showed little interaction with RET G-quadruplex and also had no effect on RET expression in MTC TT cells. The down-regulation of RET with berberine further inhibited the cell proliferation through cell cycle arrest and activation of apoptosis in TT cells, which was confirmed by a 2-fold increase in the caspase-3 activity and the down-regulation of cell-cycle regulatory proteins. CONCLUSION: Our data strongly suggest that the G-quadruplex forming region and the stabilization of this structure play a critical role in mediating the repressive effect of berberine on RET transcription.en
dc.language.isoenen
dc.publisherBioMed Central Ltden
dc.relation.urlhttp://www.biomedcentral.com/1471-2407/15/599en
dc.rights© 2015 Kumarasamy et al. Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/)en
dc.titleSelective repression of RET proto-oncogene in medullary thyroid carcinoma by a natural alkaloid berberineen
dc.typeArticleen
dc.identifier.eissn1471-2407en
dc.contributor.departmentCollege of Pharmacy, University of Arizonaen
dc.contributor.departmentBIO5 Instituteen
dc.contributor.departmentArizona Cancer Centeren
dc.identifier.journalBMC Canceren
dc.description.collectioninformationThis item is part of the UA Faculty Publications collection. For more information this item or other items in the UA Campus Repository, contact the University of Arizona Libraries at repository@u.library.arizona.edu.en
dc.eprint.versionFinal published versionen
All Items in UA Campus Repository are protected by copyright, with all rights reserved, unless otherwise indicated.