Dichloroacetate restores colorectal cancer chemosensitivity through the p53/miR-149-3p/PDK2-mediated glucose metabolic pathway.
Fiche publication
Date publication
octobre 2019
Journal
Oncogene
Auteurs
Membres identifiés du Cancéropôle Est :
Dr GAIDDON Christian, Dr GROSS Isabelle
Tous les auteurs :
Liang Y, Hou L, Li L, Li L, Zhu L, Wang Y, Huang X, Hou Y, Zhu D, Zou H, Gu Y, Weng X, Wang Y, Li Y, Wu T, Yao M, Gross I, Gaiddon C, Luo M, Wang J, Meng X
Lien Pubmed
Résumé
The development of chemoresistance remains a major challenge that accounts for colorectal cancer (CRC) lethality. Dichloroacetate (DCA) was originally used as a metabolic regulator in the treatment of metabolic diseases; here, DCA was assayed to identify the mechanisms underlying the chemoresistance of CRC. We found that DCA markedly enhanced chemosensitivity of CRC cells to fluorouracil (5-FU), and reduced the colony formation due to high levels of apoptosis. Using the microarray assay, we noted that miR-149-3p was involved in the chemoresistance of CRC, which was modulated by wild-type p53 after DCA treatment. In addition, PDK2 was identified as a direct target of miR-149-3p. Mechanistic analyses showed that overexpression of miR-149-3p enhanced 5-FU-induced apoptosis and reduced glucose metabolism, similar to the effects of PDK2 knockdown. In addition, overexpression of PDK2 partially reversed the inhibitory effect of miR-149-3p on glucose metabolism. Finally, both DCA treatment and miR-149-3p overexpression in 5-FU-resistant CRC cells were found to markedly sensitize the chemotherapeutic effect of 5-FU in vivo, and this effect was also validated in a small retrospective cohort of CRC patients. Taken together, we determined that the p53/miR-149-3p/PDK2 signaling pathway can potentially be targeted with DCA treatment to overcome chemoresistant CRC.
Référence
Oncogene. 2019 Oct 9;: