Autophagy-mediated growth inhibition of malignant glioma cells by the BH3-mimetic gossypol

Kim, Na-Yeon; Lee, Michael

doi:10.1007/s13273-014-0017-8

Cited by 5 publications

(3 citation statements)

References 24 publications

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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%

“…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).…”

Section: Introductionmentioning

confidence: 92%

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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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Section: Introductionmentioning

confidence: 86%

Section: Introductionmentioning

confidence: 92%

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-mediated macromolecular degradation contributes to building block supply, which fuels the elevated metabolism of cancer cells [6]. Our previous studies have also shown the contradictory roles that autophagy plays in both promoting and suppressing carcinogenesis [7][8][9].…”

Section: Introductionmentioning

confidence: 97%

ATG5 knockout promotes paclitaxel sensitivity in drug-resistant cells via induction of necrotic cell death

Hwang

Yeom

Lee

2020

Korean J Physiol Pharmacol

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Autophagy regulators are often effective as potential cancer therapeutic agents. Here, we investigated paclitaxel sensitivity in cells with knockout (KO) of ATG5 gene. The ATG5 KO in multidrug resistant v-Ha-ras-transformed NIH 3T3 cells (Ras-NIH 3T3/Mdr) was generated using the CRISPR/Cas9 technology. The qPCR and LC3 immunoblot confirmed knockout of the gene and protein of ATG5, respectively. The ATG5 KO restored the sensitivity of Ras-NIH 3T3/Mdr cells to paclitaxel. Interestingly, ATG5 overexpression restored autophagy function in ATG5 KO cells, but failed to rescue paclitaxel resistance. These results raise the possibility that low level of resistance to paclitaxel in ATG5 KO cells may be related to other roles of ATG5 independent of its function in autophagy. The ATG5 KO significantly induced a G 2 /M arrest in cell cycle progression. Additionally, ATG5 KO caused necrosis of a high proportion of cells after paclitaxel treatment. These data suggest that the difference in sensitivity to paclitaxel between ATG5 KO and their parental MDR cells may result from the disparity in the proportions of necrotic cells in both populations. Thus, our results demonstrate that the ATG5 KO in paclitaxel resistant cells leads to a marked G 2 /M arrest and sensitizes cells to paclitaxel-induced necrosis.

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Cell death in glioblastoma and the central nervous system

Malone,

LaCasse,

Beug

2024

Cell Oncol.

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Glioblastoma is the commonest and deadliest primary brain tumor. Glioblastoma is characterized by significant intra- and inter-tumoral heterogeneity, resistance to treatment and dismal prognoses despite decades of research in understanding its biological underpinnings. Encompassed within this heterogeneity and therapy resistance are severely dysregulated programmed cell death pathways. Glioblastomas recapitulate many neurodevelopmental and neural injury responses; in addition, glioblastoma cells are composed of multiple different transformed versions of CNS cell types. To obtain a greater understanding of the features underlying cell death regulation in glioblastoma, it is important to understand the control of cell death within the healthy CNS during homeostatic and neurodegenerative conditions. Herein, we review apoptotic control within neural stem cells, astrocytes, oligodendrocytes and neurons and compare them to glioblastoma apoptotic control. Specific focus is paid to the Inhibitor of Apoptosis proteins, which play key roles in neuroinflammation, CNS cell survival and gliomagenesis. This review will help in understanding glioblastoma as a transformed version of a heterogeneous organ composed of multiple varied cell types performing different functions and possessing different means of apoptotic control. Further, this review will help in developing more glioblastoma-specific treatment approaches and will better inform treatments looking at more direct brain delivery of therapeutic agents.

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Autophagy-mediated growth inhibition of malignant glioma cells by the BH3-mimetic gossypol

Cited by 5 publications

References 24 publications

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

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

ATG5 knockout promotes paclitaxel sensitivity in drug-resistant cells via induction of necrotic cell death

Cell death in glioblastoma and the central nervous system

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