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dc.contributor.authorKumarasamy, Vishnuen
dc.contributor.authorSun, Daekyuen
dc.date.accessioned2017-07-12T16:07:03Z
dc.date.available2017-07-12T16:07:03Z
dc.date.issued2017-05-11
dc.identifier.citationDemonstration of a potent RET transcriptional inhibitor for the treatment of medullary thyroid carcinoma based on an ellipticine derivative 2017 International Journal of Oncologyen
dc.identifier.issn1019-6439
dc.identifier.issn1791-2423
dc.identifier.doi10.3892/ijo.2017.3994
dc.identifier.urihttp://hdl.handle.net/10150/624673
dc.description.abstractDominant-activating mutations in the RET (rear-ranged during transfection) proto-oncogene, which encodes a receptor tyrosine kinase, is often associated with the development of medullary thyroid carcinoma (MTC). The proximal promoter region of the RET gene consists of a guanine-rich sequence containing five runs of three consecutive guanine residues that serve as the binding site for transcriptional factors. As we have recently shown, this stretch of nucleotides in the promoter region is highly dynamic in nature and tend to form non-B DNA secondary structures called G-quadruplexes, which suppress the transcription of the RET gene. In the present study, ellipticine and its derivatives were identified as excellent RET G-quadruplex stabilizing agents. Circular dichroism (CD) spectroscopic studies revealed that the incorporation of a piperidine ring in an ellipticine derivative, NSC311153 improves its binding with the G-quadruplex structure and the stability induced by this compound is more potent than ellipticine. Furthermore, this compound also interfered with the transcriptional mechanism of the RET gene in an MTC derived cell line, TT cells and significantly decreased the endogenous RET protein expression. We demonstrated the specificity of NSC311153 by using papillary thyroid carcinoma (PTC) cells, the TPC1 cell line which lacks the G-quadruplex forming sequence in the promoter region due to chromosomal rearrangement. The RET downregulation selectively suppresses cell proliferation by inhibiting the intracellular Raf/MEK/ERK and PI3K/Akt/mTOR signaling pathways in the TT cells. In the present study, we also showed that the systemic administration of a water soluble NSC311153 analog in a mouse MTC xenograft model inhibited the tumor growth through RET downregulation.
dc.language.isoenen
dc.publisherSPANDIDOS PUBL LTDen
dc.relation.urlhttp://www.spandidos-publications.com/10.3892/ijo.2017.3994en
dc.rights© SPANDIDOS PUBLICATIONS UK LTD.en
dc.subjectRETen
dc.subjectmedullary thyroid carcinomaen
dc.subjectellipticineen
dc.subjectG-quadruplexen
dc.titleDemonstration of a potent RET transcriptional inhibitor for the treatment of medullary thyroid carcinoma based on an ellipticine derivativeen
dc.typeArticleen
dc.contributor.departmentUniv Arizona, Coll Pharmen
dc.contributor.departmentUniv Arizona, Arizona Canc Ctren
dc.identifier.journalInternational Journal of Oncologyen
dc.description.note6 month embargo; Published online: May 11, 2017en
dc.description.collectioninformationThis item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at repository@u.library.arizona.edu.en
dc.eprint.versionFinal published versionen
dc.contributor.institutionCollege of Pharmacy, University of Arizona, Tucson, AZ 85719, USA
dc.contributor.institutionCollege of Pharmacy, University of Arizona, Tucson, AZ 85719, USA
refterms.dateFOA2017-11-12T00:00:00Z
html.description.abstractDominant-activating mutations in the RET (rear-ranged during transfection) proto-oncogene, which encodes a receptor tyrosine kinase, is often associated with the development of medullary thyroid carcinoma (MTC). The proximal promoter region of the RET gene consists of a guanine-rich sequence containing five runs of three consecutive guanine residues that serve as the binding site for transcriptional factors. As we have recently shown, this stretch of nucleotides in the promoter region is highly dynamic in nature and tend to form non-B DNA secondary structures called G-quadruplexes, which suppress the transcription of the RET gene. In the present study, ellipticine and its derivatives were identified as excellent RET G-quadruplex stabilizing agents. Circular dichroism (CD) spectroscopic studies revealed that the incorporation of a piperidine ring in an ellipticine derivative, NSC311153 improves its binding with the G-quadruplex structure and the stability induced by this compound is more potent than ellipticine. Furthermore, this compound also interfered with the transcriptional mechanism of the RET gene in an MTC derived cell line, TT cells and significantly decreased the endogenous RET protein expression. We demonstrated the specificity of NSC311153 by using papillary thyroid carcinoma (PTC) cells, the TPC1 cell line which lacks the G-quadruplex forming sequence in the promoter region due to chromosomal rearrangement. The RET downregulation selectively suppresses cell proliferation by inhibiting the intracellular Raf/MEK/ERK and PI3K/Akt/mTOR signaling pathways in the TT cells. In the present study, we also showed that the systemic administration of a water soluble NSC311153 analog in a mouse MTC xenograft model inhibited the tumor growth through RET downregulation.


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