Bafilomycin A1 targets both autophagy and apoptosis pathways in pediatric B-cell acute lymphoblastic leukemia

Yuan, Na; Lin, Shiu‐Ru; Zhang, Suping; Wei, Lin; Cao, Yan; Xu, Fei; Fang, Yixuan; Wang, Zhen; Zhang, Han; Li, Xin; Wang, Zhijian; Cai, Jinyang; Wang, Jian; Zhang, Yi; Mao, Xinliang; Zhao, Wei‐Li; Hu, Shaoyan; Chen, Suning; Wang, Jianrong

doi:10.3324/haematol.2014.113324

Cited by 144 publications

(90 citation statements)

References 50 publications

(54 reference statements)

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“…A recent report by Yuan et al showed that BafA1 at low concentration (1 nM) inhibits the early stage of autophagy by promoting mTOR activation and Beclin1 association with Bcl2 in pediatric B-cell ALL cells8. We investigate whether BafA1 at low concentration inhibits the the early stage of autophagy by promoting mTOR activation in HCC cell lines as observed in pediatric B-cell ALL cells.…”

Section: Resultsmentioning

confidence: 91%

“…Recent studies indicate that BafA1 triggers caspase-independent cell death in cancers of different origins813. Given the established role of BafA1 in blocking autophagosome-lysosome fusion during the late stage of autophagy, we hypothesized that BafA1 may target autophagy to induce cell death of HCC cells.…”

Section: Resultsmentioning

confidence: 99%

“…These data suggest that BafA1 may not induce caspase-dependent cell death in HCC cells. We also examined the expression levels of the Bcl2 family of proteins, which are reportedly involved in BafA1-induced cancer cell death8. While BafA1 treatment downregulated the levels of pro-survival proteins Bcl2 and Bcl-XL in HCC cells (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Furthermore, BafA1 activated HIF-dependent signaling in human colon cancer cells via mitochondrial uncoupling7. Consistent with the effect of BafA1 on autophagy, recent investigations demonstrated that BafA1 targets both autophagy and apoptosis pathways in pediatric B-cell acute lymphoblastic leukemia8. In addition, BafA1 has been widely used as an autophagy inhibitor to potentiate the anti-cancer effects of a large number of compounds in pre-clinical trials9.…”

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confidence: 76%

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Bafilomycin A1 induces caspase-independent cell death in hepatocellular carcinoma cells via targeting of autophagy and MAPK pathways

Yan

Jiang

Liu

et al. 2016

Sci Rep

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Hepatocellular carcinoma (HCC) is refractory to chemotherapies, necessitating novel effective agents. The lysosome inhibitor Bafilomycin A1 (BafA1) at high concentrations displays cytotoxicity in a variety of cancers. Here we show that BafA1 at nanomolar concentrations suppresses HCC cell growth in both 2 dimensional (2D) and 3D cultures. BafA1 induced cell cycle arrest in the G1 phase and triggered Cyclin D1 turnover in HCC cells in a dual-specificity tyrosine phosphorylation-regulated kinase 1B (DYRK1B) dependent manner. Notably, BafA1 induced caspase-independent cell death in HCC cells by impairing autophagy flux as demonstrated by elevated LC3 conversion and p62/SQSTM1 levels. Moreover, genetic ablation of LC3 significantly attenuated BafA1-induced cytotoxicity of HCC cells. We further demonstrate that pharmacological down-regulation or genetic depletion of p38 MAPK decreased BafA1-induced cell death via abolishment of BafA1-induced upregulation of Puma. Notably, knockdown of Puma impaired BafA1-induced HCC cell death, and overexpression of Puma enhanced BafA1-mediated HCC cell death, suggesting a role for Puma in BafA1-mediated cytotoxicity. Interestingly, pharmacological inhibition of JNK with SP600125 enhanced BafA1-mediated cytotoxicity both in vitro and in xenografts derived from HCC cells. Taken together, our data suggest that BafA1 may offer potential as an effective therapy for HCC.

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Section: Resultsmentioning

confidence: 91%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 76%

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Bafilomycin A1 induces caspase-independent cell death in hepatocellular carcinoma cells via targeting of autophagy and MAPK pathways

Yan

Jiang

Liu

et al. 2016

Sci Rep

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“…8 In contrast, autophagy was important for long-term NP cell survival, possibly due to overall inhibition of the protein degradation machinery and accumulation of misfolded proteins resulting in ER stress. 74,75 It is important to note that aberrant changes in autophagy are involved in the pathogenesis of many diseases as well as normal aging. 76,77 An altered level of autophagy during intervertebral disc degeneration and aging has been reported.…”

Section: Discussionmentioning

confidence: 99%

Hypoxia promotes noncanonical autophagy in nucleus pulposus cells independent of MTOR and HIF1A signaling

et al. 2016

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Nucleus pulposus (NP) cells reside in the avascular and hypoxic microenvironment of intervertebral discs. Importantly, many activities related to survival and function of NP cells are controlled by the HIF-family of transcription factors. We hypothesize that NP cells adapt to their hypoxic niche through modulation of macroautophagy/autophagy. In various cell types, hypoxia induces autophagy in a HIF1A-dependent fashion; however, little is known about hypoxic regulation of autophagy in NP cells. Hypoxia increases the number of autophagosomes as seen by TEM analysis and LC3-positive puncta in NP cells. Hypoxic induction of autophagy was also demonstrated by a significantly higher number of autophagosomes and smaller change in autolysosomes in NP cells expressing tandem-mCherry-EGFP-LC3B. Increased LC3-II levels were not accompanied by a concomitant increase in BECN1 or the ATG12-ATG5 complex. In addition, ULK1 phosphorylation at Ser757 and Ser777 responsive to MTOR and AMPK, respectively, was not affected in hypoxia. Interestingly, when MTOR activity was inhibited by rapamycin or Torin1, LC3-II levels did not change, suggesting a novel MTOR-independent regulation. Noteworthy, while silencing of HIF1A affected hypoxic induction of BNIP3, it did not affect LC3-II levels, indicating hypoxia-induced autophagy is HIF1-independent. Importantly, there was no change in the number of LC3-positive autophagosomes in NP-specific Hif1a null mice. Finally, inhibition of autophagic flux did not affect the glycolytic metabolism of NP cells, suggesting a possible nonmetabolic role of autophagy. Taken together, our study for the first time shows that NP cells regulate autophagy in a noncanonical fashion independent of MTOR and HIF1A signaling.

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Inhibition of silkworm vacuolar‐type ATPase activity by its inhibitor Bafilomycin A1 induces caspase‐dependent apoptosis in an embryonic cell line of silkworm

Tan

Wang

Liu

et al. 2018

Arch Insect Biochem Physiol

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Vacuolar‐type ATPase (V‐ATPase) is a type of hydrogen ion transporter located in the vesicular membrane‐like system, which mediates active transport and intracellular acidification in various compartments. In mammals, V‐ATPase has been reported to play a key role in cell proliferation and apoptosis. The studies of V‐ATPase in silkworm mainly focus on the acidification regulation of midgut and silk gland and immune resistance. However, there are few reports about the function of silkworm V‐ATPase on cell proliferation, autophagy, and apoptosis. Thus, the function of V‐ATPase in a cell line of Bombyx mori (BmE) was investigated by treating the cell line with bafilomycin A1, a specific inhibitor of V‐ATPase. Cell counting kit 8 (CCK8) and flow cytometry analysis showed that bafilomycin A1 treatment decreased the cell proliferation activity, affected the cell cycle progression and induced cell apoptosis. LysoTracker Red staining showed that the target of bafilomycin A1 is lysosome. The expression of all autophagy‐related genes ( BmATG5, BmATG6, and BmATG8) decreased, indicating that cell autophagy was inhibited. The analysis of the apoptosis pathway demonstrated that inhibiting the activity of V‐ATPase of BmE cells could promote mitochondria to release cytochrome C, inhibit the expression of BmIAP, and activate the caspase cascade to induce apoptosis. All these findings systematically illustrate the effects of V‐ATPase on the proliferation, autophagy, and apoptosis in BmE cells, and provide new ideas and a theoretical basis for further study on the function of V‐ATPase in BmE.

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Bafilomycin A1 targets both autophagy and apoptosis pathways in pediatric B-cell acute lymphoblastic leukemia

Abstract: ABSTRACTmechanism or have tumor suppressive functions, depending on the context. In addition, autophagy is involved in other important aspects of blood cancers as it promotes immune competence and anticancer immunity, and may even help to enhance patients' tolerance to standard treatments.

Cited by 144 publications

References 50 publications

Bafilomycin A1 induces caspase-independent cell death in hepatocellular carcinoma cells via targeting of autophagy and MAPK pathways

Bafilomycin A1 induces caspase-independent cell death in hepatocellular carcinoma cells via targeting of autophagy and MAPK pathways

Hypoxia promotes noncanonical autophagy in nucleus pulposus cells independent of MTOR and HIF1A signaling

Inhibition of silkworm vacuolar‐type ATPase activity by its inhibitor Bafilomycin A1 induces caspase‐dependent apoptosis in an embryonic cell line of silkworm

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