Selective repression of RET proto-oncogene in medullary thyroid carcinoma by a natural alkaloid berberineReport as inadecuate

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BMC Cancer

, 15:599

First Online: 26 August 2015Received: 18 December 2014Accepted: 18 August 2015DOI: 10.1186-s12885-015-1610-5

Cite this article as: Kumarasamy, V.M., Shin, YJ., White, J. et al. BMC Cancer 2015 15: 599. doi:10.1186-s12885-015-1610-5


BackgroundThe 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.

MethodsMedullary 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.

ResultsBerberine 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.

ConclusionOur 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.

AbbreviationsMTCMedullary Thyroid Carcinoma

PTCPapillary Thyroid Carcinoma

DMSDimethyl Sulfate

ChIPChromatin Immuno-precipitation

CCD6Coiled-coil Domain containing gene 6

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Author: Vishnu Muthuraj Kumarasamy - Yoon-Joo Shin - John White - Daekyu Sun



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