Metformin induces ZFP36 by mTORC1 inhibition in cervical cancer-derived cell lines.

Autor: De la Cruz-López KG; Programa de Doctorado en Ciencias Biomédicas, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Mexico City, Mexico.; Laboratorio de Virus y Cáncer, Unidad de Investigación Biomédica en Cáncer. Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México & Instituto Nacional de Cancerología., Av. San Fernando No. 22 Colonia Sección XVI, Tlalpan, Mexico City, 14080, Mexico., Alvarado-Ortiz E; Departamento de Bioquímica, Facultad de Medicina, Universidad Nacional Autónoma de México, Mexico City, Mexico., Valencia-González HA; Laboratorio de Células Troncales y Desarrollo Terapéutico Antineoplásico, Subdirección de Investigación Básica, Instituto Nacional de Cancerología, Secretaría de Salud, Mexico City, Mexico., Beltrán-Anaya FO; Laboratorio de Diagnóstico e Investigación en Salud, Facultad de Ciencias Químico-Biológicas, Universidad Autónoma de Guerrero, Chilpancingo de los Bravo, Gro, Mexico., Zamora-Fuentes JM; Laboratorio de Oncología Teórica, Instituto Nacional de Medicina Genómica, Mexico City, Mexico.; Centro de Ciencias de La Complejidad, Universidad Nacional Autónoma de México, Mexico City, Mexico., Hidalgo-Miranda A; Laboratorio de Genómica de Cáncer, Instituto Nacional de Medicina Genómica, Mexico City, Mexico., Ortiz-Sánchez E; Laboratorio de Células Troncales y Desarrollo Terapéutico Antineoplásico, Subdirección de Investigación Básica, Instituto Nacional de Cancerología, Secretaría de Salud, Mexico City, Mexico., Espinal-Enríquez J; Laboratorio de Oncología Teórica, Instituto Nacional de Medicina Genómica, Mexico City, Mexico.; Centro de Ciencias de La Complejidad, Universidad Nacional Autónoma de México, Mexico City, Mexico., García-Carrancá A; Laboratorio de Virus y Cáncer, Unidad de Investigación Biomédica en Cáncer. Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México & Instituto Nacional de Cancerología., Av. San Fernando No. 22 Colonia Sección XVI, Tlalpan, Mexico City, 14080, Mexico. carranca@iibiomedicas.unam.mx.
Jazyk: angličtina
Zdroj: BMC cancer [BMC Cancer] 2024 Jul 18; Vol. 24 (1), pp. 853. Date of Electronic Publication: 2024 Jul 18.
DOI: 10.1186/s12885-024-12555-5
Abstrakt: Background: Metformin, a widely prescribed antidiabetic drug, has shown several promising effects for cancer treatment. These effects have been shown to be mediated by dual modulation of the AMPK-mTORC1 axis, where AMPK acts upstream of mTORC1 to decrease its activity. Nevertheless, alternative pathways have been recently discovered suggesting that metformin can act through of different targets regulation.
Methods: We performed a transcriptome screening analysis using HeLa xenograft tumors generated in NOD-SCID mice treated with or without metformin to examine genes regulated by metformin. Western Blot analysis, Immunohistochemical staining, and RT-qPCR were used to confirm alterations in gene expression. The TNMplot and GEPIA2 platform were used for in silico analysis of genes found up-regulated by metformin, in cervical cancer patients. We performed an AMPK knock-down using AMPK-targeted siRNAs and mTOR inhibition with rapamycin to investigate the molecular mechanisms underlying the effect of metformin in cervical cancer cell lines.
Results: We shown that metformin decreases tumor growth and increased the expression of a group of antitumoral genes involved in DNA-binding transcription activator activity, hormonal response, and Dcp1-Dcp2 mRNA-decapping complex. We demonstrated that ZFP36 could act as a new molecular target increased by metformin. mTORC1 inhibition using rapamycin induces ZFP36 expression, which could suggest that metformin increases ZFP36 expression and requires mTORC1 inhibition for such effect. Surprisingly, in HeLa cells AMPK inhibition did not affect ZFP36 expression, suggesting that additional signal transducers related to suppressing mTORC1 activity, could be involved.
Conclusions: These results highlight the importance of ZFP36 activation in response to metformin treatment involving mTORC1 inhibition.
(© 2024. The Author(s).)
Databáze: MEDLINE
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