A novel role for nonactin: interfering with G-quadruplex in RET-driven medullary thyroid cancer.

Publisher: BioMed Central Country of Publication: England NLM ID: 100967800 Publication Model: Electronic Cited Medium: Internet ISSN: 1471-2407 (Electronic) Linking ISSN: 14712407 NLM ISO Abbreviation: BMC Cancer Subsets: MEDLINE

Original Publication: London : BioMed Central, [2001-

Proto-Oncogene Proteins c-ret*/genetics ; Proto-Oncogene Proteins c-ret*/metabolism ; Proto-Oncogene Proteins c-ret*/antagonists & inhibitors ; G-Quadruplexes*/drug effects ; Thyroid Neoplasms*/drug therapy ; Thyroid Neoplasms*/genetics ; Thyroid Neoplasms*/metabolism ; Thyroid Neoplasms*/pathology ; Proto-Oncogene Mas* ; Carcinoma, Neuroendocrine*/genetics ; Carcinoma, Neuroendocrine*/drug therapy; Humans ; Cell Line, Tumor ; Apoptosis/drug effects ; Cell Proliferation/drug effects ; Mutation ; Promoter Regions, Genetic ; High-Throughput Screening Assays

Background: Medullary Thyroid Carcinoma (MTC) is closely associated with mutations in the RET proto-oncogene, placing the activated RET protein at the center of MTC pathogenesis. Existing therapeutic solutions, primarily tyrosine kinase inhibitors such as selpercatinib, vandetanib, and cabozantinib, have shown moderate efficacy but are accompanied by increased risks of side effects and resistance. This study unveils a promising avenue using nonactin, a compound historically recognized for its antibacterial properties, targeting the G-quadruplex interactions within the RET proto-oncogene.
Method: In this research, high-throughput screening was conducted using a luciferase reporter-based cellular assay. The MTC TT cell line was treated with nonactin for 24 and 48 h. Immunoblotting and RT-PCR were employed to measure the protein and RNA levels of RET and its downstream stream proteins. Binding to the G-Quadruplex was assessed using melting curves and Circular Dichroism. The cell cycle was analyzed using FACS, and caspase activity was measured to indicate the activation of apoptosis.
Results: Nonactin was identified to significantly reduce luciferase activity driven by the RET promoter. A deeper exploration revealed nonactin's remarkable selectivity against tumor cell lines harboring RET mutations, effectively inducing apoptosis. Nonactin was also found to bind to the G-quadruplex region on RET.
Conclusion: The findings highlight the compound's therapeutic potential, emphasizing its mechanism of inducing apoptosis in active mutant RET cell lines by interacting with G-quadruplex structures. This novel insight opens avenues for a potentially effective treatment for MTC, potentially bypassing the challenges associated with current TKIs.
Competing Interests: Declarations. Ethics approval and consent to participate: Not applicable. Consent for publication: Not applicable. Competing interests: The authors declare no competing interests.
(© 2024. The Author(s).)

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SP22R/239/09 KAIMRC; SP22R/239/09 KAIMRC; SP22R/239/09 KAIMRC; SP22R/239/09 KAIMRC; SP22R/239/09 KAIMRC; SP22R/239/09 KAIMRC; SP22R/239/09 KAIMRC; SP22R/239/09 KAIMRC

Keywords: Drug design; G-quadruplex; Medullary thyroid carcinoma; Nonactin; RET

EC 2.7.10.1 (Proto-Oncogene Proteins c-ret)
0 (Proto-Oncogene Mas)
EC 2.7.10.1 (RET protein, human)
0 (MAS1 protein, human)

Thyroid cancer, medullary

Date Created: 20241223 Date Completed: 20241224 Latest Revision: 20250104

20250114

PMC11665027

10.1186/s12885-024-13345-9

39716145