Rapamycin-induced autophagy plays a pro-survival role by enhancing up-regulation of intracellular ferritin expression in acute lymphoblastic leukemia

• Datum: 2023
• Hauptverfasser: Gong, Y., Wu, J., Yang, R., Zhang, L., Ma, Z.
• Format: Artikel
• Sprache: English
• Veröffentlicht: PH Akademperiodyka 2023
• Schlagworte: acute lymphoblastic leukemia; autophagy; ciclopirox olamine; ferritin; rapamycin
• Online Zugang: https://exp-oncology.com.ua/index.php/Exp/article/view/2020-1-3
• Назва журналу: Experimental Oncology

Summary. Elevated mammalian target of rapamycin (mTOR) signaling has been reported to correlate with poor prognosis in acute lymphoblastic leukemia (ALL) patients. Rapamycin, an mTOR kinase inhibitor, and also a potent autophagy inducer, could not only effectively reverse glucocorticoid resistance, but also promote autophagy in the ALL cells. Autophagy has been suggested to play a paradoxical role in cancer treatment. The aim of this study was to address the role of the rapamycin-induced autophagy in the leukemia treatment. Materials and Methods: Cell proliferation was detected by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay in ALL cell lines of CEM-C1 and CEM-C7. Western Blot analysis was performed to test protein expressions. Results: Inhibition of mTOR by rapamycin could reverse glucocorticoid resistance in CEM-C1 cells, and also induce autophagy in these cells by up-regulation of LC3-II and Beclin-1 expressions. This autophagy played a pro-survival role since its inhibition by 6-amino-3-methylpurine or chroloquine could enhance rapamycin-induced cell death. Rapamycin increased the expression of intracellular ferritin, and this effect could be totally blocked by 6-amino-3-methylpurine and chroloquine, suggesting that the protective role of autophagy might be mediated through up-regulation of ferritin, the major iron-binding stress protein. Ciclopirox olamine, an iron chelator, could enhance rapamycin’s anti-leukemia effect by down-regulation of intracellular ferritin expression. Conclusions: All these findings would suggest that rapamycin-induced autophagy plays a pro-survival role in leukemia cells and this effect might be mediated by up-regulation of intracellular ferritin expression. We hypothesize that the combination of mTOR pathway inhibitors and autophagy inhibition is rational and would induce strong anti-leukemia effects in ALL.