Salinomycin and its derivatives as potent RET transcriptional inhibitors for the treatment of medullary thyroid carcinoma

Tariq Alqahtani, Vishnu Muthuraj Kumarasamy, Adam Huczyński, Daekyu Sun

Research output: Contribution to journalArticle

Abstract

Rearranged during transfection kinase (RET) is a validated molecular target in medullary thyroid cancer (MTC), as activating mutations in RET are often associated with the development of MTC. The present study reports the first preclinical characterization of salinomycin and selected analogs as potent RET transcriptional inhibitors. Reverse transcription-PCR and immunoblotting revealed that salinomycin profoundly decreased RET expression in the TT human MTC cell line by inhibiting RET transcription. Moreover, salinomycin resulted in remarkable anti-proliferative activity against MTC that is driven by RET (gain of function mutation) by selectively inhibiting the intracellular PI3K/Akt/mTOR signaling pathway. Also, flow cytometry and fluorescence-activated cell sorting showed that salinomycin induces G1 phase arrest and apoptosis by reducing the expression of retinoblastoma protein, E2F1, cyclin D and CDK4. The structure-activity relationship of salinomycin was investigated in this study. Some of the salinomycin derivatives showed the ability to reduce RET expression where others fail to alter RET expression. These results suggest that the RET-suppressing effect of salinomycin may be largely attributed to disruption of the Wnt pathway, presumably through interference with the ternary LRP6-Frizzled-Wnt complex. Furthermore, these findings support the further preclinical evaluation of salinomycin and its analogs as a promising new class of therapeutic agents for the improved treatment of MTC.

Original languageEnglish (US)
Pages (from-to)348-358
Number of pages11
JournalInternational journal of oncology
Volume56
Issue number1
DOIs
Publication statusPublished - Jan 1 2020

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Keywords

  • Medullary thyroid carcinoma
  • RET
  • Salinomycin
  • Wnt signaling

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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