FOXO3a in cancer drug resistance.

The role of endolysosomal trafficking in anticancer drug resistance

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.

/pdf/mir-199a-5p-represses-protective-autophagy-and-overcomes-1ai1cebsu2.pdf

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

Autophagy plays critical roles in tumorigenesis, while the effects of autophagy on chemoresistance of cancer cells had great disparity. This study aims to explore the impacts of autophagy on the se...

/pdf/inhibition-of-autophagy-improves-resistance-and-enhances-1u7a63x6hy.pdf

Inhibition of autophagy improves resistance and enhances sensitivity of gastric cancer cells to cisplatin.

Repurposing drugs in autophagy for the treatment of cancer: From bench to bedside

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.

/pdf/hydroxychloroquine-reverses-the-drug-resistance-of-leukemic-9swag7c5f5.pdf

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

Patients with acute myeloid leukemia (AML) often have a poor prognosis due to drug resistance, which is regarded as a tough problem during the period of clinical therapeutics. It has been reported that autophagy, an important event in various cellular processes, plays a crucial role in mediating drug-resistance to cancer cells. Our study attempts to comparatively investigate the differences of basic and induced autophagic activity between drug-sensitive and multidrug-resistant AML cells. The level of basic autophagy in K562/ADM cells was higher than that in K562 cells, which could be characterized by more cytosolic contents-packaged autophagic vacuoles in K562/ADM cells when compared to that in K562 cells. The observation of MDC staining showed that the fluorescent intensity of autophagosomes in K562/ADM cells was stronger than that in K562 cells. The expression of Beclin1 and the ratio of LC3-II to LC3-I were distinctly higher in K562/ADM cells, however, P62 protein was relatively lower in K562/ADM cells. Furthermore, we found that nutrient depletion could induce autophagic activity of both cell lines. However, autophagic activity of K562/ADM cells was always maintained at a higher level in contrast with K562 cells. ADM (Adriamycin) was also capable of inducing autophagic activity of K562 and K562/ADM cells, but the autophagic alteration in K562 cells appeared earlier. Taken together, our findings suggest that autophagy exerts an important effect on formation and maintenance of drug-resistance in AML cells.

http://www.jstage.jst.go.jp/article/irdr/6/4/6_2017.01069/_pdf

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

Skeletal homeostasis is dynamically influenced by the immune system. Low density lipoprotein receptor-related protein-5 (LRP5) is a co-receptor of the Wnt signaling pathway, which modulates bone metabolism in humans and mice. Immune disorders can lead to abnormal bone metabolism. It is unclear whether and how LRP5 alters the balance of the immune system to modulate bone homeostasis. In this study, we used primary osteoblast to detect the differentiation of osteoblasts in vitro, the immune cells of spleen and bone marrow of 6-month old LRP5 heterozygote (HZ) and wild-type (WT) mice were analyzed by Flow cytometry. We found that LRP5+/- could influence the differentiation of osteoblasts by decreasing the mRNA level of Osterix, and increasing the mRNA level of Runx2 and the ratio of receptor activator for nuclear factor-κB ligand/osteoprotegerin (RANKL/OPG). In the LRP5+/- mice, percentages of NK cells, CD3e+ cells, and CD8a+ T cells were increased in both spleen and bone marrow, and percentages of CD106+ cells and CD11c+ cells were increased in spleen while decreased in bone marrow, conversely, CD62L+ cells were decreased in spleen while increased in bone marrow compared to the WT mice. Percentages of CD4+ cells, CD14+ cells, and CD254+ cells were increased in the spleen, and CTLA4+ cells were increased in the bone marrow of the LRP5+/- mice. The mRNA level of Wnt signaling molecules such as β-catenin, and c-myc were decreased and APC was increased in spleen lymphocytes and bone marrow lymphocytes, and the mRNA level of Wnt3a was decreased in spleen lymphocytes while no change in bone marrow lymphocytes was seen with silencing LRP5 by specific small interfering RNA. In conclusion, heterozygous deletion of the LRP5 gene in mice could alter the profile of the immune cells, influence the balance of immune environment, and modulate bone homeostasis, which might present a potential mechanism to explore the Wnt signaling pathway in the modulation of the immune system.

Heterozygous deletion of LRP5 gene in mice alters profile of immune cells and modulates differentiation of osteoblasts

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

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

Heterozygous deletion of LRP5 gene in mice alters profile of immune cells and modulates differentiation of osteoblasts