The development of several medullary thyroid carcinomas is strongly associated with the gain-of-function mutation of the RET proto-oncogene, which encodes a receptor tyrosine kinase, so that the RET protein has been regarded as a potential therapeutic target for the treatment of progressive and advanced MTC. In our study we have explored a new strategy to repress the transcription of the RET proto-oncogene in MTC using small molecules. Interestingly, we found that a natural product berberine inhibits the RET gene transcription by specifically targeting the promoter region of this gene, thereby reducing the RET protein expression in MTC TT cells. The down-regulation of RET with berberine also results in the suppression of cell proliferation through cell cycle arrest and activation of apoptosis in TT cells. Overall, our results strongly suggest that berberine stabilizes G-quadruplexes formed from the G-rich sequence present on the promoter region of this gene and the stabilization of this structure play a critical role in mediating the repressive effect of berberine on RET transcription.

Citation Format: Daekyu Sun, Vishnu Kumarasamy. A natural alkaloid, berberine, as a novel transcriptional repressor of RET proto-oncogene in medullary thyroid carcinoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5546. doi:10.1158/1538-7445.AM2015-5546