Cytoprotective role of autophagy against BH3 mimetic gossypol in ATG5 knockout cells generated by CRISPR-Cas9 endonuclease

Kim, Na-Yeon; Han, Byeal-I; Lee, Michael

doi:10.1016/j.canlet.2015.10.008

Cited by 15 publications

(11 citation statements)

References 34 publications

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“…Previous studies suggest that autophagy can be accurately regulated by autophagy-related genes [ 14 ]. Among these ATG genes, ATG5 protein in a conjugated form with ATG12 and ATG8 (LC3) are associated with the early stages of autophagosome formation [ 15 , 16 ]. A growing number of studies have demonstrated that autophagy is related to the pathogenesis of many diseases, including cancer, infections, diabetes, and neurodegenerative disorders [ 17 ].…”

Section: Discussionmentioning

confidence: 99%

Liraglutide Enhances Autophagy and Promotes Pancreatic β Cell Proliferation to Ameliorate Type 2 Diabetes in High-Fat-Fed and Streptozotocin-Treated Mice

et al. 2018

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BackgroundClinical and experimental studies have revealed that liraglutide has multiple anti-diabetes biological effects. However, little is known about its role in autophagy and pancreatic β cell proliferation. This study aimed to assessed the effects of liraglutide on pancreatic β cell proliferation and autophagy in a mouse model of type 2 diabetes.Material/MethodsThe effect of liraglutide on autophagy and proliferation in pancreatic β cells was investigated using a high-fat-fed and streptozotocin-induced mouse model of type 2 diabetes.ResultsLiraglutide significantly improved the symptoms of high-fat-fed (HFD) and streptozotocin (STZ)-induced type 2 diabetic mice, as indicated by body weight gain, reduction of blood glucose and plasma insulin, and enhanced sensitivity to insulin. The results of quantitative real-time polymerase chain reaction and Western blot analysis showed that liraglutide upregulated AGT5 expression and promoted the conversion of LC3-I to LC3-II, thus improving the defective autophagy. In addition, we observed that both mRNA and protein expressions of PCNA and Ki-67 were upregulated by liraglutide treatment. Immunocytochemical staining results showed that the number of PCNA- or Ki-67-positive cells in pancreatic islet tissues in the HFD + STZ + liraglutide group were increased compared with the HFD + STZ group.ConclusionsThese results strongly suggest that liraglutide is able to enhance autophagy and promote pancreatic β cell proliferation. This study improves our insights into the mechanism by which liraglutide treatment relieves diabetes, and provides experimental evidence for clinical utilization of liraglutide in type 2 diabetes treatment.

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Section: Discussionmentioning

confidence: 99%

Liraglutide Enhances Autophagy and Promotes Pancreatic β Cell Proliferation to Ameliorate Type 2 Diabetes in High-Fat-Fed and Streptozotocin-Treated Mice

et al. 2018

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“…Our previous studies also showed that autophagy can serve either pro‐survival or ‐death functions (Ahn, Lee, Ahn, & Lee, ; Kim & Lee, ; Kim, Han, & Lee, ). We recently reported a cytoprotective role of autophagy against BH3 mimetic gossypol in melanoma cells and glioma cells (Kim & Lee, ; Kim et al, ). Conversely, we found that an inhibitor (UAI‐201) of oncogenic protein BRAF induces cell cycle arrest and autophagy in BRAF‐mutant glioma cells (Ahn et al, ).…”

Section: Introductionmentioning

confidence: 86%

Knockout of ATG5 leads to malignant cell transformation and resistance to Src family kinase inhibitor PP2

Hwang

Han

Lee

2017

Journal Cellular Physiology

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Autophagy can either promote or inhibit cell death in different cellular contexts. In this study, we investigated the role of autophagy in ATG5 knockout (KO) cell line established using CRISPR/ Cas9 system. In ATG5 KO cells, RT-PCR and immunoblot of LC3 confirmed the functional gene knockout. We found that knockout of ATG5 significantly increased proliferation of NIH 3T3 cells. In particular, autophagy deficiency enhanced susceptibility to cellular transformation as determined by an in vitro clonogenic survival assay and a soft agar colony formation assay. We also found that ATG5 KO cells had a greater migration ability as compared to wild-type (WT) cells. Moreover, ATG5 KO cells were more resistant to treatment with a Src family tyrosine kinase inhibitor (PP2) than WT cells were. Cyto-ID Green autophagy assay revealed that PP2 failed to induce autophagy in ATG5 KO cells. PP2 treatment decreased the percentage of cells in the S and G 2 /M phases among WT cells but had no effect on cell cycle distribution of ATG5 KO cells, which showed a high percentage of cells in the S and G 2 /M phases. Additionally, the proportion of apoptotic cells significantly decreased after treatment of ATG5 KO cells with PP2 in comparison with WT cells. We found that expression levels of p53 were much higher in ATG5 KO cells. The ATG5 KO seems to lead to compensatory upregulation of the p53 protein because of a decreased apoptosis rate. Taken together, our results suggest that autophagy deficiency can lead to malignant cell transformation and resistance to PP2.Autophagy is a crucial adaptive response that functions as a primary route of degradation for long-lived proteins and cytoplasmic organelles during normal cellular homeostasis (Mizushima & Komatsu, 2011). Nonetheless, there are conflicting data on the involvement of autophagy in the regulation of cell death or survival. In fact, autophagy can either promote or inhibit cell death in different cellular contexts (Maycotte & Thorburn, 2011; White et al., 2011). Our previous studies also showed that autophagy can serve either pro-survival or -death functions (Ahn, Lee, Ahn, & Lee, 2014;Kim & Lee, 2014;Kim, Han, & Lee, 2016). We recently reported a cytoprotective role of autophagy against BH3 mimetic gossypol in melanoma cells and glioma cells (Kim & Lee, 2014;Kim et al., 2016). Conversely, we found that an inhibitor (UAI-201) of oncogenic protein BRAF induces cell cycle arrest and autophagy in BRAF-mutant glioma cells (Ahn et al., 2014). In particular, deletion of ATG5 in mice results in the development of a benign tumor in the liver (Takamura et al., 2011), suggesting that autophagy has tumor-suppressive effects.Src family kinases (SFKs) are kept in an inactive state but can be switched to an active state by abnormal events such as a mutation (Okada, 2012). Active forms of SFKs are central mediators in multiple signaling pathways that are important in oncogenesis (Kim, Song, & Haura, 2009). Thus, Src inhibition has been proposed recently as a strategy for cancer therapy (Kim et al., 2...

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“…For instance, Torin1 and AZD8055 can induce phagosome formation, thereby promoting autophagy . Similarly, other autophagy‐associated structures such as the autophagosome and autolysosome can also be modulated by agents such as gossypol, suberoylanilide hydroxamic acid, resveratrol, and 3,4,5‐trimethyl‐1,3‐thiazol‐3‐ium . For interference to function of autolysosome, CQ and HCQ have been used for the treatment of malaria, RA and SLE, and clinical trials have shown that they block autophagy by inhibiting lysosomal proteases .…”

Section: Autophagy‐associated Modulatorsmentioning

confidence: 99%

“…265,292 Similarly, other autophagy-associated structures such as the autophagosome and autolysosome can also be modulated by agents such as gossypol, suberoylanilide hydroxamic acid, resveratrol, and 3,4,5-trimethyl-1,3thiazol-3-ium. [293][294][295][296] For interference to function of autolysosome, CQ and HCQ have been used for the treatment of malaria, RA and SLE, and clinical trials have shown that they block autophagy by inhibiting lysosomal proteases. [297][298][299][300] During these processes, the accumulation of autophagy vacuoles can be observed by electron microscopy, and autophagy-associated markers such as LC3B, SQSTM1, MAP1LC3A and the ratio of LC3B-II/ LC3B-I are significantly altered, while cargo digestion is significantly inhibited.…”

mentioning

confidence: 99%

Modulation of autophagy in human diseases strategies to foster strengths and circumvent weaknesses

Sui

Zhang

et al. 2019

Medicinal Research Reviews

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Autophagy is central to the maintenance of intracellular homeostasis across species. Accordingly, autophagy disorders are linked to a variety of diseases from the embryonic stage until death, and the role of autophagy as a therapeutic target has been widely recognized. However, autophagy‐associated therapy for human diseases is still in its infancy and is supported by limited evidence. In this review, we summarize the landscape of autophagy‐associated diseases and current autophagy modulators. Furthermore, we investigate the existing autophagy‐associated clinical trials, analyze the obstacles that limit their progress, offer tactics that may allow barriers to be overcome along the way and then discuss the therapeutic potential of autophagy modulators in clinical applications.

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Cytoprotective role of autophagy against BH3 mimetic gossypol in ATG5 knockout cells generated by CRISPR-Cas9 endonuclease

Cited by 15 publications

References 34 publications

Liraglutide Enhances Autophagy and Promotes Pancreatic β Cell Proliferation to Ameliorate Type 2 Diabetes in High-Fat-Fed and Streptozotocin-Treated Mice

Liraglutide Enhances Autophagy and Promotes Pancreatic β Cell Proliferation to Ameliorate Type 2 Diabetes in High-Fat-Fed and Streptozotocin-Treated Mice

Knockout of ATG5 leads to malignant cell transformation and resistance to Src family kinase inhibitor PP2

Modulation of autophagy in human diseases strategies to foster strengths and circumvent weaknesses

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