Autophagy prevents doxorubicin-induced apoptosis in osteosarcoma

Zhao, Dongxu; Yuan, Hongping; Yi, Fei; Meng, Chunyang; Zhu, Qiang

doi:10.3892/mmr.2014.2055

Cited by 37 publications

(35 citation statements)

References 29 publications

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“…The inhibition of autophagy with 3MA reduced calpain activation and virus replication (24) and induced apoptosis in colon cancer cells (25). Autophagy inhibitor 3-MA, alone or combined with doxorubicin, induced apoptosis in osteosarcoma (26). Chloroquine is widely used as an antimalarial drug that interferes with hemozoin formation (27).…”

Section: Discussionmentioning

confidence: 99%

Autophagy Inhibitors as a Potential Antiamoebic Treatment for Acanthamoeba Keratitis

Moon

Kim

Hong

et al. 2015

Antimicrob Agents Chemother

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bAcanthamoeba cysts are resistant to extreme physical and chemical conditions. Autophagy is an essential pathway for encystation of Acanthamoeba cells. To evaluate the possibility of an autophagic Acanthamoeba encystation mechanism, we evaluated autophagy inhibitors, such as 3-methyladenine (3MA), LY294002, wortmannin, bafilomycin A, and chloroquine. Among these autophagy inhibitors, the use of 3MA and chloroquine showed a significant reduction in the encystation ratio in Acanthamoeba cells. Wortmannin also inhibited the formation of mature cysts, while LY294002 and bafilomycin A did not affect the encystation of Acanthamoeba cells. Transmission electron microscopy revealed that 3MA and wortmannin inhibited autophagy formation and that chloroquine interfered with the formation of autolysosomes. Inhibition of autophagy or autolysosome formation resulted in a significant block in the encystation in Acanthamoeba cells. Clinical treatment with 0.02% polyhexamethylene biguanide (PHMB) showed high cytopathic effects on Acanthamoeba trophozoites and cysts; however, it also revealed high cytopathic effects on human corneal epithelial cells. In this study, we investigated effects of the combination of a low (0.00125%) concentration of PHMB with each of the autophagy inhibitors 3MA, wortmannin, and chloroquine on Acanthamoeba and human corneal epithelial cells. These new combination treatments showed low cytopathic effects on human corneal cells and high cytopathic effects on Acanthamoeba cells. Taken together, these results provide fundamental information for optimizing the treatment of Acanthamoeba keratitis.A canthamoeba trophozoites differentiate into cysts under conditions of physical stresses, starvation, and chemical exposure (1-3); the cysts are resistant to several chemical biocides (4). Resistance of the cysts to chemotherapeutic drugs makes the treatment of Acanthamoeba infections difficult (4, 5). Although polyhexamethylene biguanide (PHMB) (0.02%), alone or in combination with a diamidine (0.1% propamidine or 0.1% hexamidine), showed therapeutic efficacy against Acanthamoeba keratitis (6), PHMB was reported to be cytotoxic to human corneal epithelial (HCE) cells (7). Although therapy for Acanthamoeba keratitis needs better-acting drugs, due to the encystation of Acanthamoeba cells, cytotoxicity toward mammalian cells must also be considered.Recent studies have demonstrated anticancer therapies that include autophagy targeting in different tumor cell lines (8, 9). One change in the cellular composition during the encystation of protozoa is the formation of an autophagy (10). The biological significance of autophagy associated with starvation, differentiation, development, and immunity has been previously demonstrated (10-13). In Acanthamoeba cells, several genes associated with autophagy, including those encoding Atg8, Atg8 isoform, Atg3, and Atg16L, were identified and their roles in the encystation of Acanthamoeba cells were studied (14-17). Autophagy is a major cellular pathway for the encystation of Acanth...

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Section: Discussionmentioning

confidence: 99%

Autophagy Inhibitors as a Potential Antiamoebic Treatment for Acanthamoeba Keratitis

Moon

Kim

Hong

et al. 2015

Antimicrob Agents Chemother

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“…Doxorubicin treatment has been shown to induce autophagy in several cancer models. [40][41][42] However, we observed a decrease in the protein levels of ATG5, ATG7, LC3A-II and LC3B-II, as well as mRNA levels of ATG5, ATG7, ATG12, BECN1 and ULK1, and an increase in the protein levels of p- Rapamycin and serum starvation-treated cells were subjected to (H) WB analysis and rapamycin-treated cells were subjected to (I) qRT-PCR analysis for pluripotency factors (POU5F1, NANOG, SOX2). Rapamycin and serum starvation-treated cells were subjected to (J) WB analysis and rapamycin-treated cells were subjected to (K) qRT-PCR analysis for differentiation markers (TUBB3, CSN2, SPP1, GATA6, T, CDX2).…”

Section: Autophagy-driven Decrease In Pluripotency Is Coupled With Anmentioning

confidence: 99%

Autophagic homeostasis is required for the pluripotency of cancer stem cells

et al. 2016

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Pluripotency is an important feature of cancer stem cells (CSCs) that contributes to self-renewal and chemoresistance. The maintenance of pluripotency of CSCs under various pathophysiological conditions requires a complex interaction between various cellular pathways including those involved in homeostasis and energy metabolism. However, the exact mechanisms that maintain the CSC pluripotency remain poorly understood. In this report, using both human and murine models of CSCs, we demonstrate that basal levels of autophagy are required to maintain the pluripotency of CSCs, and that this process is differentially regulated by the rate-limiting enzyme in the NAD C synthesis pathway NAMPT (nicotinamide phosphoribosyltransferase) and the transcription factor POU5F1/OCT4 (POU class 5 homeobox 1). First, our data show that the pharmacological inhibition and knockdown (K D ) of NAMPT or the K D of POU5F1 in human CSCs significantly decreased the expression of pluripotency markers POU5F1, NANOG (Nanog homeobox) and SOX2 (SRY-box 2), and upregulated the differentiation markers TUBB3 (tubulin b 3 class III), CSN2 (casein b), SPP1 (secreted phosphoprotein 1), GATA6 (GATA binding protein 6), T (T brachyury transcription factor) and CDX2 (caudal type homeobox 2). Interestingly, these pluripotency-regulating effects of NAMPT and POU5F1 were accompanied by contrasting levels of autophagy, wherein NAMPT K D promoted while POU5F1 K D inhibited the autophagy machinery. Most importantly, any deviation from the basal level of autophagy, either increase (via rapamycin, serum starvation or Tat-beclin 1 [Tat-BECN1] peptide) or decrease (via ATG7 or ATG12 K D ), strongly decreased the pluripotency and promoted the differentiation and/or senescence of CSCs. Collectively, these results uncover the link between the NAD C biosynthesis pathway, CSC transcription factor POU5F1 and pluripotency, and further identify autophagy as a novel regulator of pluripotency of CSCs.

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“…Accordingly, intrinsic resistance to Dox and DDP through autophagic activity has been certified in osteosarcoma cells (17). Therefore, since miR-410 directly targeted ATG16L1 in osteosarcoma cancer cells, it was hypothesized that miR-410 may be able to reverse chemoresistance via autophagy inhibition.…”

Section: Resultsmentioning

confidence: 99%

MicroRNA-410 regulates autophagy-related gene ATG16L1 expression and enhances chemosensitivity via autophagy inhibition in osteosarcoma

Ren

et al. 2017

Molecular Medicine Reports

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Osteosarcoma, which is the most common type of primary bone tumor in adolescents, is characterized by complex genetic alterations and frequent resistance to conventional treatments. MicroRNAs (miRs) have emerged as fundamental regulators in gene expression through their ability to silence gene expression at post-transcriptional and translational levels. The present study investigated the role of miR-410 in the progression of osteosarcoma. The results demonstrated that the expression of miR-410 was markedly downregulated in human osteosarcoma tissues, and U2OS and MG-63 osteosarcoma cell lines. Clinicopathological significance suggested that miR-410 may be a potential biomarker for chemotherapy-resistant osteosarcoma. Furthermore, overexpression of miR-410 exhibited a limited effect on cell viability in U2OS and MG-63 cells. Target prediction algorithms (TargetScan and miRanda) indicated that autophagy related 16-like 1 (ATG16L1) was a potential target gene of miR-410. A luciferase reporter assay demonstrated that miR-410 directly decreased ATG16L1 expression by targeting its 3′-untranslated region. In addition, the results revealed that miR-410 was able to markedly inhibit autophagy. Accordingly, autophagy was activated as a protective mechanism when osteosarcoma cells were exposed to three common anticancer drugs, including rapamycin, doxorubicin and cisplatin. Furthermore, the autophagy inhibitor 3-methyladenine and miR-410 expression were able to improve the therapeutic response of the cells to chemotherapy drugs (rapamycin, doxorubicin and cisplatin), thus indicating that miR-410 enhanced chemosensitivity through autophagy inhibition in osteosarcoma cells. In conclusion, studies regarding the function of miR-410 on autophagy provided insight into the biological function of miR-410 in osteosarcoma and may offer a promising approach for the treatment of osteosarcoma.

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Autophagy prevents doxorubicin-induced apoptosis in osteosarcoma

Cited by 37 publications

References 29 publications

Autophagy Inhibitors as a Potential Antiamoebic Treatment for Acanthamoeba Keratitis

Autophagy Inhibitors as a Potential Antiamoebic Treatment for Acanthamoeba Keratitis

Autophagic homeostasis is required for the pluripotency of cancer stem cells

MicroRNA-410 regulates autophagy-related gene ATG16L1 expression and enhances chemosensitivity via autophagy inhibition in osteosarcoma

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