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

Yan, Yumei; Jiang, Ke; Liu, Peng; Zhang, Xianbin; Dong, Xin; Gao, Jingchun; Liu, Quentin; Barr, Martin P.; Zhang, Quan; Liu, Yangcheng; Shao, Meng; Gong, Peng

doi:10.1038/srep37052

Cited by 94 publications

(61 citation statements)

References 20 publications

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“…However, Yan et al used lowdose bafilomycin A1 to block autophagic flux, which also triggered cyclin D1 turnover, but in a DYRK1Bdependent fashion, leading to the caspase-independent death of HCC cells. (25) Based on our findings and other reports, it appears that either induction or suppression of autophagy activation could trigger cyclin D1 turnover, but through different signaling pathways, which further determine the fate of the cells. Altogether, suppression of cell-cycle progression through autophagy-regulated cyclin D1 turnover may have potential as an effective therapy for HCC.…”

Section: Discussionsupporting

confidence: 72%

Hepatocellular carcinoma–related cyclin D1 is selectively regulated by autophagy degradation system

Lan

et al. 2018

Hepatology

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Dysfunction of degradation machineries causes cancers, including hepatocellular carcinoma (HCC). Overexpression of cyclin D1 in HCC has been reported. We previously reported that autophagy preferentially recruits and degrades the oncogenic microRNA (miR)‐224 to prevent HCC. Therefore, in the present study, we attempted to clarify whether cyclin D1 is another oncogenic factor selectively regulated by autophagy in HCC tumorigenesis. Initially, we found an inverse correlation between low autophagic activity and high cyclin D1 expression in tumors of 147 HCC patients and three murine models, and these results taken together revealed a correlation with poor overall survival of HCC patients, indicating the importance of these two events in HCC development. We found that increased autophagic activity leads to cyclin D1 ubiquitination and selective recruitment to the autophagosome (AP) mediated by a specific receptor, sequestosome 1 (SQSTM1), followed by fusion with lysosome and degradation. Autophagy‐selective degradation of ubiquitinated cyclin D1 through SQSTM1 was confirmed using cyclin D1/ubiquitin binding site (K33‐238R) and phosphorylation site (T286A) mutants, lentivirus‐mediated silencing autophagy‐related 5 (ATG5), autophagy‐related 7 (ATG7), and Sqstm1 knockout cells. Functional studies revealed that autophagy‐selective degradation of cyclin D1 plays suppressive roles in cell proliferation, colony, and liver tumor formation. Notably, an increase of autophagic activity by pharmacological inducers (amiodarone and rapamycin) significantly suppressed tumor growth in both the orthotopic liver tumor and subcutaneous tumor xenograft models. Our findings provide evidence of the underlying mechanism involved in the regulation of cyclin D1 by selective autophagy to prevent tumor formation. Conclusion: Taken together, our data demonstrate that autophagic degradation machinery and the cell‐cycle regulator, cyclin D1, are linked to HCC tumorigenesis. We believe these findings may be of value in the development of alternative therapeutics for HCC patients. (Hepatology 2018;68:141‐154).

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Section: Discussionsupporting

confidence: 72%

Hepatocellular carcinoma–related cyclin D1 is selectively regulated by autophagy degradation system

Lan

et al. 2018

Hepatology

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“…As for tumor cells, V‐ATPase is a key regulator of intracellular acidification. Researchers have found that Baf‐A1 is involved in arresting the cell cycle in G1 phase, causing apoptosis, and inhibiting autophagy in a dose‐dependent manner (Yan et al, ; Yuan et al, ). In contrast, the current study showed that Baf‐A1 promoted the transition from the G1 phase to the S phase in BmE cells, so the percentage of cells in S and G 2 /M phases increased.…”

Section: Discussionmentioning

confidence: 99%

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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“…However, when using inhibitors, limitations arise in determining the suitable concentration for efficient autophagy inhibition, without severely affecting cell viability. The major limitation when using inhibitors is, however, the occurrence of potential off-target or adverse effects, which could lead to misleading results 31,32 .…”

Section: Discussionmentioning

confidence: 99%

siRNA Electroporation to Modulate Autophagy in Herpes Simplex Virus Type 1-Infected Monocyte-Derived Dendritic Cells

Düthorn

Turan

Draßner

et al. 2019

JoVE

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Herpes simplex virus type-1 (HSV-1) induces autophagy in both, immature dendritic cells (iDCs) as well as mature dendritic cells (mDCs), whereas autophagic flux is only observed in iDCs. To gain mechanistic insights, we developed efficient strategies to interfere with HSV-1-induced autophagic turnover. An inhibitor-based strategy, to modulate HSV-1-induced autophagy, constitutes the first choice, since it is an easy and fast method. To circumvent potential unspecific off-target effects of such compounds, we developed an alternative siRNA-based strategy, to modulate autophagic turnover in iDCs upon HSV-1 infection. Indeed, electroporation of iDCs with FIP200-specific siRNA prior to HSV-1 infection is a very specific and successful method to ablate FIP200 protein expression and thereby to inhibit autophagic flux. Both presented methods result in the efficient inhibition of HSV-1-induced autophagic turnover in iDCs, whereby the siRNA-based technique is more target specific. An additional siRNA-based approach was developed to selectively silence the protein expression of KIF1B and KIF2A, facilitating autophagic turnover upon HSV-1 infection in mDCs. In conclusion, the technique of siRNA electroporation represents a promising strategy, to selectively ablate the expression of distinct proteins and to analyze their influence upon an HSV-1 infection.

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

Cited by 94 publications

References 20 publications

Hepatocellular carcinoma–related cyclin D1 is selectively regulated by autophagy degradation system

Hepatocellular carcinoma–related cyclin D1 is selectively regulated by autophagy degradation system

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

siRNA Electroporation to Modulate Autophagy in Herpes Simplex Virus Type 1-Infected Monocyte-Derived Dendritic Cells

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