Differences of basic and induced autophagic activity between K562 and K562/ADM cells

Wang, Feifei; Chen, Jing; Zhang, Zhewen; Yi, Juan; Yuan, Min‐Min; Wang, Mingyan; Zhang, Na; Wei, Hulai

doi:10.5582/irdr.2017.01069

Cited by 7 publications

(8 citation statements)

References 42 publications

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“…We found that miR-199a-5p was downregulated, accompanied by an elevated autophagy level, in K562/ADM cells compared to parent cells. Consistent with the reported results by Wang et al [46], we identified that the basic autophagy level and the ADM-induced autophagic activity in K562/ADM cells was higher than that in K562 cells, indicating that K562/ADM cells possess potent resistance to extra stressors. Furthermore, administration of miR-199a-5p mimics in K562/ADM cells markedly suppressed the expression of autophagy-related genes and sensitized the cells to ADM-induced cytotoxicity.…”

Section: Discussionsupporting

confidence: 93%

miR-199a-5p Represses Protective Autophagy and Overcomes Chemoresistance by Directly Targeting DRAM1 in Acute Myeloid Leukemia

Yang

Zhang

et al. 2019

Journal of Oncology

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Chemotherapy resistance is still a primary clinical obstacle to the successful treatment of acute myeloid leukemia (AML). The underlying mechanisms of drug resistance are complicated and have not been fully understood. Here, we found that miR-199a-5p levels were significantly reduced in refractory/relapsed AML patients compared to those who achieved complete remission after chemotherapy. Consistently, miR-199a-5p was markedly decreased in Adriamycin-resistant AML K562/ADM cells in contrast with Adriamycin-sensitive K562 cells, and its decrement dramatically correlated with the chemoresistance of AML cells. Furthermore, we demonstrated that the basic and Adriamycin-induced autophagic activity in K562/ADM cells was higher than that in K562 cells. This inducible autophagy played a prosurvival role and contributed to the development of acquired drug resistance. Importantly, we investigated that miR-199a-5p could negatively regulate autophagy, at least in part, by inhibiting damage regulator autophagy modulator (DRAM1) expression at both the transcriptional and posttranscriptional level. miR-199a-5p bound directly to the 3′-UTR of DRAM1 mRNA which was a functional target of miR-199a-5p. Indeed, downregulation of DRAM1 gene by siRNA in K562/ADM cells resulted in autophagy suppression and chemosensitivity restoration. These results revealed that the miR-199a-5p/DRAM1/autophagy signaling represented a novel pathway regulating chemoresistance, indicating a potential therapeutic strategy for the intervention in drug-resistant AML.

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Section: Discussionsupporting

confidence: 93%

miR-199a-5p Represses Protective Autophagy and Overcomes Chemoresistance by Directly Targeting DRAM1 in Acute Myeloid Leukemia

Yang

Zhang

et al. 2019

Journal of Oncology

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“…in addition, it was identified that basic autophagy activity in K562/ADM cells was distinctly higher than it was in K562 cells, which suggests that autophagy may be involved in multidrug resistance. This result is consistent with our previous study (27).…”

Section: Discussionsupporting

confidence: 94%

“…To further verify the results described above, other autophagic indicators were examined, such as lc3 and P62 (also known as sequestosome-1). as we know, the ratio of LC3-Ⅱ to LC3-Ⅰ will become larger when the quantity of autophagosomes increases, and P62, a ubiquitination substrate, has a contrary relationship with autophagic activity (27). as presented in Fig.…”

Section: Resultsmentioning

confidence: 91%

“…in our previous study, it was determined that multidrug-resistant leukaemia cells (K562/adM cells) demonstrated a higher level of autophagy than drug-sensitive leukaemia cells (K562 cells), both at the basic metabolic state and when under nutrient deprivation stress, implying that autophagy is associated with the drug resistance of leukaemia cells (27). To clarify the mechanism of drug resistance in leukaemia cells, hydroxychloroquine (HcQ), a classic autophagy inhibitor, was used to reverse the drug resistance of K562/adM cells, increase their apoptosis level and inhibit their P-gp expression.…”

Section: Hydroxychloroquine Reverses the Drug Resistance Of Leukemic K562/adm Cells By Inhibiting Autophagymentioning

confidence: 98%

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Hydroxychloroquine reverses the drug resistance of leukemic K562/ADM�cells by inhibiting autophagy

et al. 2019

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autophagy is an essential metabolic pathway mediated by lysosomal degradation, which is involved in scavenging and recycling senescent or damaged organelles and biological macromolecules in eukaryotic cells. The present study explored the association between the autophagic activity and chemotherapy resistance of leukaemia cells, and the possibility of using autophagy inhibitors to combat leukemic drug resistance. it was found that the levels of basic autophagy in multidrug-resistant leukaemia cells (K562/adM) were significantly higher compared with sensitive cells (K562), and that adriamycin (adM) was capable of inducing autophagic activity in K562 and K562/adM cells. K562 and K562/adM cells were treated with a series of hydroxychloroquine (HcQ) concentrations to inhibit cellular autophagy and detect cell sensitivity to adM. The results demonstrated that the sensitivity of K562 cells to adM was mildly enhanced by HcQ, and that the sensitivity of K562/adM cells to adM was markedly strengthened by HcQ. in addition, more typical morphological changes associated with apoptosis emerged, and the ratio of Bax/Bcl-2 and activity of caspase-3 were markedly increased in K562/adM cells treated with HcQ. notably, the expression of mdr1 mrna and P-glycoprotein (P-gp) in drug-resistant K562/adM cells was upregulated along with increasing autophagic activity induced by adM. Furthermore, HcQ significantly reduced the increase in P-gp expression by inhibiting autophagic activity. Collectively, these findings indicated that the inhibition of autophagy significantly promoted the sensitivity of K562/adM cells to adM by facilitating apoptosis. Furthermore, inhibition of autophagy attenuated the expression of P-gp; therefore, P-gp may be involved in autophagic regulation in drug-resistant cells.

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“…To select an appropriate AdM concentration, a pre-experiment was performed. According to a previous study (22), following AdM treatment (0.1, 0.2, 0.4, 0.6 and 0.8 µmol/ml), the activity of K562 cells was significantly inhibited (Fig. 1A, left panel).…”

Section: Discussionsupporting

confidence: 67%

MicroRNA‑145 promotes the apoptosis of leukemic�stem�cells and enhances drug‑resistant K562/ADM cell�sensitivity to adriamycin via the regulation of ABCE1

Wuxiao

Wang

et al. 2020

Int J Mol Med

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Leukemia is a type of cancer which originates in blood-forming tissues. MicroRNAs (miRNAs or miRs) have been shown to be involved leukemogenesis. In the present study, following the gain- and loss-function of miR-145 and ATP-binding cassette sub-family E member 1 (ABCE1) in K562 cells and K562 adriamycin-resistant cells (K562/ADM cells), the levels of multidrug resistance protein 1 (MRP1) and P-glycoprotein (P-gp) were measured. The viability of the K562 cells and K562/ADM cells treated with various concentrations of ADM, and cell sensitivity to ADM were measured. The apoptosis of stem cells was detected. K562/ADM cells were transfected with miR-145 mimic or with miR-145 mimic together with ABCE1 overexpression plasmid to examine the effects of ABCE1 on the sensitivity of K562/ADM cells to ADM. The association between miR-145 and ABCE1/MRP1 was then verified. The dose- and time-dependent effects of ADM on the K562 cells and K562/ADM cells were examined. The K562/ADM cells exhibited a greater resistance to ADM, higher levels of MRP1 and P-gp, and a lower miR-145 expression. The K562/ADM cells and stem cells in which miR-145 was overexpressed exhibited a suppressed cell proliferation, decreased MRP1 and P-gp levels, and an increased apoptotic rate. However, K562 cells with a low expression of miR-145 exhibited an increased cell proliferation, increased levels of MRP1 and P-gp, and a suppressed apoptotic rate. Compared with the overexpression of miR-145, the combination of miR-145 and ABCE1 decreased the sensitivity of drug-resistant K562/ADM cells to ADM. The above-mentioned effects of miR-145 were achieved by targeting ABCE1. Taken together, the findings of the present study demonstrate that the overexpression of miR-145 promotes leukemic stem cell apoptosis and enhances the sensitivity of K562/ADM cells to ADM by inhibiting ABCE1.

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Differences of basic and induced autophagic activity between K562 and K562/ADM cells

Cited by 7 publications

References 42 publications

miR-199a-5p Represses Protective Autophagy and Overcomes Chemoresistance by Directly Targeting DRAM1 in Acute Myeloid Leukemia

miR-199a-5p Represses Protective Autophagy and Overcomes Chemoresistance by Directly Targeting DRAM1 in Acute Myeloid Leukemia

Hydroxychloroquine reverses the drug resistance of leukemic K562/ADM�cells by inhibiting autophagy

MicroRNA‑145 promotes the apoptosis of leukemic�stem�cells and enhances drug‑resistant K562/ADM cell�sensitivity to adriamycin via the regulation of ABCE1

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