00085472can131748-sup-fig_1.pdf (37.28 kB)
Supplementary Figure 1 from Inhibition of miR-17 and miR-20a by Oridonin Triggers Apoptosis and Reverses Chemoresistance by Derepressing BIM-S
journal contributionposted on 2023-03-30, 22:27 authored by Hengyou Weng, Huilin Huang, Bowen Dong, Panpan Zhao, Hui Zhou, Lianghu Qu
PDF file - 33KB, Oridonin induces BIM-S in multiple leukemia cell lines.
ARTICLE ABSTRACTCancer cell chemoresistance arises in part through the acquisition of apoptotic resistance. Leukemia cells resistant to chemotherapy-induced apoptosis have been found to be sensitive to oridonin, a natural agent with potent anticancer activity. To investigate its mechanisms of action in reversing chemoresistance, we compared the response of human leukemia cells with oridonin and the antileukemia drugs Ara-C and VP-16. Compared with HL60 cells, K562 and K562/ADR cells displayed resistance to apoptosis stimulated by Ara-C and VP-16 but sensitivity to oridonin. Mechanistic investigations revealed that oridonin upregulated BIM-S by diminishing the expression of miR-17 and miR-20a, leading to mitochondria-dependent apoptosis. In contrast, neither Ara-C nor VP-16 could reduce miR-17 and miR-20a expression or could trigger BIM-S–mediated apoptosis. Notably, silencing miR-17 or miR-20a expression by treatment with microRNA (miRNA; miR) inhibitors or oridonin restored sensitivity of K562 cells to VP-16. Synergistic effects of oridonin and VP-16 were documented in cultured cells as well as mouse tumor xenograft assays. Inhibiting miR-17 or miR-20a also augmented the proapoptotic activity of oridonin. Taken together, our results identify a miRNA-dependent mechanism underlying the anticancer effect of oridonin and provide a rationale for its combination with chemotherapy drugs in addressing chemoresistant leukemia cells. Cancer Res; 74(16); 4409–19. ©2014 AACR.
Cell Death And Senescencebcl-2 pathwaysChemotherapyCombination chemotherapyComputational MethodsGene expression profilingDrug MechanismsDrug-mediated stimulation of cell death pathwaysDrug ResistanceReversal of drug resistanceGene RegulationPosttranscriptional and translational controlPreclinical ModelsXenograft models