The dual roles of autophagy in gliomagenesis and clinical therapy strategies based on autophagic regulation mechanisms

Fěng, Fang; Zhang, Moxuan; Yang, Chuanchao; Heng, Xueyuan; Wu, Xiujie

doi:10.1016/j.biopha.2019.109441

Cited by 35 publications

(34 citation statements)

References 104 publications

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“…Previous studies have proved the important role of autophagy in tumorigenesis and treatment [ 16 ]. Autophagy is the process of transporting damaged [ 17 ], denatured, or aged proteins and organelles to lysosomes for digestion and degradation, which circulates and degrades intracellular components in response to a lack of nutrients or growth factors to maintain homeostasis [ 18 ].…”

Section: Introductionmentioning

confidence: 99%

Arctigenin Inhibits Glioblastoma Proliferation through the AKT/mTOR Pathway and Induces Autophagy

Jiang

Liu

Wangwang

et al. 2020

BioMed Research International

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Purpose. Arctigenin (ARG) is a natural lignan compound extracted from Arctium lappa and has displayed anticancer function and therapeutic effect in a variety of cancers. Arctigenin is mainly from Arctium lappa extract. It has been shown to induce autophagy in various cancers. However, as for whether arctigenin induces autophagy in gliomas or not, the specific mechanism is still worth exploring. Methods. Using CCK8, the monoclonal experiment was made to detect the proliferation ability. The scratch experiment and the transwell experiment were applied to the migration and invasion ability. PI/RNase and FITC-conjugated anti-annexin V were used to detect the cell cycle and apoptosis. Western blotting was used to determine the specified protein level, and constructed LC3B-GFP plasmid was used for analysis of autophagy.Results. Our research showed that ARG inhibited the growth and proliferation and invasion and migration of glioma cells in a dose-dependent manner (U87MG and T98G) and arrested the cell cycle and induced apoptosis. Interestingly, ARG induced autophagy in a dose-dependent manner. We applied Western blotting to measure the increase in the key autophagy protein LC3B, as well as some other autophagy-related proteins (increase in Beclin-1 and decrease in P62). In order to further explore the mechanism that ARG passed initiating autophagy to inhibit cell growth, we further found by Western blotting that AKT and mTOR phosphorylation proteins (P-AKT, P-mTOR) were reduced after ARG treatment, and we used AKT agonists to rescue, and the phosphorylated proteins of AKT and mTOR increased, and we found that the autophagy-related proteins were also reversed. And interestingly, the protein of apoptosis was also reversed along with autophagy. Conclusions. We thought ARG inhibited the proliferation of glioma cells by inducing autophagy and apoptosis through the AKT/mTOR pathway.

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Section: Introductionmentioning

confidence: 99%

Arctigenin Inhibits Glioblastoma Proliferation through the AKT/mTOR Pathway and Induces Autophagy

Jiang

Liu

Wangwang

et al. 2020

BioMed Research International

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“…Local recurrence or metastases after therapy failure in patients with early-stage carcinoma are common. Emerging evidence indicates that autophagy plays the critical roles in the development of local recurrence after therapy failure in human cancers (7)(8)(9). Our findings indicate that TRPM8 is a universal master regulator of basal autophagy that maintains and regulates the level of basal autophagy in several types of mammalian cancer cells.…”

Section: Discussionmentioning

confidence: 64%

“…Increasing evidence indicates that basal autophagy plays the critical roles in the development of local recurrence after therapy failure in human cancer (7)(8)(9). Autophagy is a highly conserved self-degradative process that functions as a cell survival mechanism during cellular stress responses, such as starvation, hypoxia, and chemo/radiotherapy (10,11).…”

Section: Introductionmentioning

confidence: 99%

Transient Receptor Potential Melastatin 8 (TRPM8) Channel Regulates Proliferation and Migration of Breast Cancer Cells by Activating the AMPK-ULK1 Pathway to Enhance Basal Autophagy

et al. 2020

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The calcium-permeable cation channel TRPM8 (transient receptor potential melastatin 8) is a member of the TRP superfamily of cation channels that is upregulated in various types of cancer with high levels of autophagy, including prostate, pancreatic, breast, lung, and colon cancers. Autophagy is closely regulated by AMP-activated protein kinase (AMPK) and plays an important role in tumor growth by generating nutrients through degradation of intracellular structures. Additionally, AMPK activity is regulated by intracellular Ca2+ concentration. Considering that TRPM8 is a non-selective Ca2+-permeable cation channel and plays a key role in calcium homoeostasis, we hypothesized that TRPM8 may control AMPK activity thus modulating cellular autophagy to regulate the proliferation and migration of breast cancer cells. In this study, overexpression of TRPM8 enhanced the level of basal autophagy, whereas TRPM8 knockdown reduced the level of basal autophagy in several types of mammalian cancer cells. Moreover, the activity of the TRPM8 channel modulated the level of basal autophagy. The mechanism of regulation of autophagy by TRPM8 involves autophagy-associated signaling pathways for activation of AMPK and ULK1 and phagophore formation. Impaired AMPK abolished TRPM8-dependent regulation of autophagy. TRPM8 interacts with AMPK in a protein complex, and cytoplasmic C-terminus of TRPM8 mediates the TRPM8–AMPK interaction. Finally, basal autophagy mediates the regulatory effects of TRPM8 on the proliferation and migration of breast cancer cells. Thus, this study identifies TRPM8 as a novel regulator of basal autophagy in cancer cells acting by interacting with AMPK, which in turn activates AMPK to activate ULK1 in a coordinated cascade of TRPM8-mediated breast cancer progression.

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“…GJ/CDDP combination treatment showed enhanced autophagic flux, and by co-treatment of the pan-caspase inhibitor Z-VAD-FMK, we could conclude the apoptotic effect of GJ/CDDP combination was related to the induction of autophagy. To elucidate the underlying mechanism of this action, we investigated the AKT/mTOR pathway, the well-known pathway which regulates autophagy and also plays a key role in cell survival/death of gliomas [74]. Our results indicated that this pathway is crucial for the apoptotic action of GJ/CDDP combination in U87MG and U373MG GBM cells.…”

Section: Discussionmentioning

confidence: 92%

Gardenia jasminoides Enhances CDDP-Induced Apoptosis of Glioblastoma Cells via AKT/mTOR Pathway While Protecting Death of Astrocytes

Kim

Hong

et al. 2020

Nutrients

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Gliomas are the most observed primary brain tumor, of which glioblastoma multiform (GBM) shows the highest incidence. Radiotherapy with temozolomide is the standard therapeutic method, but because of side effects, search for alternative therapies is required. Gardenia jasminoides (GJ) is flavonoid abundant with beneficial effects on inflammation, metabolic diseases, and cancers. In this study, we investigated the synergistic combination of GJ and cisplatin (CDDP) in U87MG and U373MG GBM cells. GJ and CDDP both showed cytotoxicity in U87MG cells, however GJ did not affect viability of normal astrocytes while CDDP displayed high toxicity. Cytotoxic effect of GJ and CDDP was related in apoptosis when confirmed by Western blot assays on cleaved caspase-3, caspase-9, and PARP. Moreover, GJ and CDDP showed synergistic combination in cell death of GBM cells, which was further confirmed by Western blot assays of apoptosis factors and also flow cytometry of Annexin V. Analysis on autophagy factors showed that GJ/CDDP combination induced autophagy, and through inhibition of autophagy, we could confirm autophagy is crucial to cytotoxicity of GJ/CDDP in GBM cell lines. The autophagy-mediated apoptosis of GJ/CDDP was dependent on the AKT/mTOR pathway. Overall, our results suggest GJ/CDDP combination as an effective yet safe therapeutic approach to GBMs.

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The dual roles of autophagy in gliomagenesis and clinical therapy strategies based on autophagic regulation mechanisms

Cited by 35 publications

References 104 publications

Arctigenin Inhibits Glioblastoma Proliferation through the AKT/mTOR Pathway and Induces Autophagy

Arctigenin Inhibits Glioblastoma Proliferation through the AKT/mTOR Pathway and Induces Autophagy

Transient Receptor Potential Melastatin 8 (TRPM8) Channel Regulates Proliferation and Migration of Breast Cancer Cells by Activating the AMPK-ULK1 Pathway to Enhance Basal Autophagy

Gardenia jasminoides Enhances CDDP-Induced Apoptosis of Glioblastoma Cells via AKT/mTOR Pathway While Protecting Death of Astrocytes

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