Rapamycin-induced autophagy plays a pro-survival role by enhancing up-regulation of intracellular ferritin expression in acute lymphoblastic leukemia / Y. Gong [et al.] // Experimental Oncology. - 2020. - Том 42, N 1. - P11-15 MeSH-главная: ЛЕЙКОЗ-ЛИМФОМА ПРЕ-КЛЕТОЧНЫЙ ЛИМФОБЛАСТНЫЙ -- PRECURSOR CELL LYMPHOBLASTIC LEUKEMIA-LYMPHOMA (патофизиология) Аннотация: 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 Доп.точки доступа: Gong, Y. Wu, J. Yang, R. Zhang, L. Ma, Z. Свободных экз. нет