Inhibition of glioma growth by flavokawain B is mediated through endoplasmic reticulum stress induced autophagy

Wang, Jiwei; Qi, Qichao; Zhou, Wenjing; Feng, Zichao; Huang, Bin; Chen, Anjing; Zhang, Di; Li, Wenjie; Zhang, Qing; Jiang, Zheng; Bjerkvig, Rolf; Prestegarden, Lars; Thorsen, Frits; Wang, Xinyu; Li, Xingang; Wang, Jian

doi:10.1080/15548627.2018.1501133

Cited by 97 publications

(68 citation statements)

References 40 publications

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“…These results were confirmed by Annexin V/PI analysis. Moreover, to confirm the role of autophagy in cancer cell death, we analysed both synergism and apoptosis in the presence of 3-metyladenin (3-MA), which is a widely used autophagy inhibitor [37,60]. Differently from chloroquine and bafilomycin A, 3-MA inhibits autophagosomes formation at early stages.…”

Section: Discussionmentioning

confidence: 99%

“…Differently from chloroquine and bafilomycin A, 3-MA inhibits autophagosomes formation at early stages. For these reasons, 3-MA has been widely used in similar experiments [38,60]. In these experimental conditions, synergism was completely prevented and cell viability increased from about 27% in polydatin/ lapatinib-treated cells to about 50% in the presence of 3-MA.…”

Section: Discussionmentioning

confidence: 99%

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Glucose-6-phosphate dehydrogenase blockade potentiates tyrosine kinase inhibitor effect on breast cancer cells through autophagy perturbation

Mele

Noce

Paino

et al. 2019

J Exp Clin Cancer Res

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Background: Glucose-6-phospate dehydrogenase (G6PD) is the limiting enzyme of the pentose phosphate pathway (PPP) correlated to cancer progression and drug resistance. We previously showed that G6PD inhibition leads to Endoplasmic Reticulum (ER) stress often associated to autophagy deregulation. The latter can be induced by target-based agents such as Lapatinib, an anti-HER2 tyrosine kinase inhibitor (TKI) largely used in breast cancer treatment. Methods: Here we investigate whether G6PD inhibition causes autophagy alteration, which can potentiate Lapatinib effect on cancer cells. Immunofluorescence and flow cytometry for LC3B and lysosomes tracker were used to study autophagy in cells treated with lapatinib and/or G6PD inhibitors (polydatin). Immunoblots for LC3B and p62 were performed to confirm autophagy flux analyses together with puncta and colocalization studies. We generated a cell line overexpressing G6PD and performed synergism studies on cell growth inhibition induced by Lapatinib and Polydatin using the median effect by Chou-Talay. Synergism studies were additionally validated with apoptosis analysis by annexin V/PI staining in the presence or absence of autophagy blockers. Results: We found that the inhibition of G6PD induced endoplasmic reticulum stress, which was responsible for the deregulation of autophagy flux. Indeed, G6PD blockade caused a consistent increase of autophagosomes formation independently from mTOR status. Cells engineered to overexpress G6PD became resilient to autophagy and resistant to lapatinib. On the other hand, G6PD inhibition synergistically increased lapatinib-induced cytotoxic effect on cancer cells, while autophagy blockade abolished this effect. Finally, in silico studies showed a significant correlation between G6PD expression and tumour relapse/resistance in patients. Conclusions: These results point out that autophagy and PPP are crucial players in TKI resistance, and highlight a peculiar vulnerability of breast cancer cells, where impairment of metabolic pathways and autophagy could be used to reinforce TKI efficacy in cancer treatment.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Glucose-6-phosphate dehydrogenase blockade potentiates tyrosine kinase inhibitor effect on breast cancer cells through autophagy perturbation

Mele

Noce

Paino

et al. 2019

J Exp Clin Cancer Res

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“…Cristacarpin, a known isoflavonoid isolated from Erythrina suberosa stem bark, enhanced ER stress with increased expressions of GRP-94 and PERK by activation of p38, thereby generating sub-lethal ROS, elevating the expression of p21 waf1 in a p53-independent manner, and reducing the expressions of Cdk-2 and cyclinD1, which in turn caused cellular senescence through G1 phase cell cycle arrest in pancreatic and breast cancer cells [80]. After treatment with flavokawain B, a flavonoid compound, approximately 60% of human glioblastoma multiforme cells became senescent and this result was attributed to ER stress-dependent autophagy, which was regulated by ATF-4/DNA damage inducible transcript 3 (DDIT3)/tribbles pseudokinase 3 (TRIB3)/mTOR signaling pathway [81]. Penta-1,2,3,4,6-Ogalloyl-β-d-glucose, a phenolic acid compound, triggered autophagy and activated ERN1 and EIF2AK3 arms of UPR signaling pathways to promote senescence both in cancer cells and a xenograft mouse model of human HepG2 liver cancer [82].…”

Section: Endoplasmic Reticulum (Er) Stress-induced Senescencementioning

confidence: 99%

Natural Polyphenols Targeting Senescence: A Novel Prevention and Therapy Strategy for Cancer

Bian

Wei

Zhao

et al. 2020

IJMS

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Cancer is one of the most serious diseases endangering human health. In view of the side effects caused by chemotherapy and radiotherapy, it is necessary to develop low-toxic anti-cancer compounds. Polyphenols are natural compounds with anti-cancer properties and their application is a considerable choice. Pro-senescence therapy is a recently proposed anti-cancer strategy and has been shown to effectively inhibit cancer. It is of great significance to clarify the mechanisms of polyphenols on tumor suppression by inducing senescence. In this review, we delineated the characteristics of senescent cells, and summarized the mechanisms of polyphenols targeting tumor microenvironment and inducing cancer cell senescence for cancer prevention and therapy. Although many studies have shown that polyphenols effectively inhibit cancer by targeting senescence, it warrants further investigation in preclinical and clinical studies.

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“…Transmission electron microscopy (TEM) was performed following Wang et al 19 After treatment with either NC or 4-PBA, the morphology of organelles was observed by TEM.…”

Section: Transmission Electron Microscopymentioning

confidence: 99%

Nitidine Chloride Is a Potential Alternative Therapy for Glioma Through Inducing Endoplasmic Reticulum Stress and Alleviating Epithelial-Mesenchymal Transition

et al. 2020

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Background: Malignant glioma is a lethal brain tumor that is highly resistant to standard therapy. Our research aims to explore the suppressive effects of nitidine chloride (NC) on gliomas and the mechanisms involved, showing that it is a potential agent for integrative therapy of gliomas. Methods: After glioma cells were treated with NC, several experiments were performed to evaluate NC's antitumor effects. CCK-8 assay was used to detect viability. Transwell and 3-dimensional spheroid invasion assays were used to evaluate motility of glioma in vitro, and the sphere-formation assay showed NC's influence on glioma stem cells. Apoptosis and intracellular reactive oxygen species were measured by means of flow cytometry. Subcellular structures were observed through transmission electron microscopy. Western blot analysis reflected expression of endoplasmic reticulum (ER) stress and epithelial-mesenchymal transition (EMT) marker proteins. An orthotopic xenograft model was established to investigate the tumor suppressive effects in vivo. Results: Nitidine chloride inhibited glioma cell migration and invasion in vitro, downregulated the EMT proteins, and suppressed sphere formation of glioma stem cells. Furthermore, NC induced persistent ER stress that contributed to apoptosis and reactive oxygen species production. The xenograft model showed that NC effectively restricted glioma growth and invasion in vivo. Furthermore, we confirmed the signaling pathways that ER stress downregulates C/EBPβ and slug, as well as inhibition of the AKT/GSK3β/β-catenin axis caused by NC, in U-87 MG. Conclusion: We demonstrated that NC inhibits gliomas in vitro and in vivo by activating ER stress and downregulating EMT, which provides a basis for glioma therapy.

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Inhibition of glioma growth by flavokawain B is mediated through endoplasmic reticulum stress induced autophagy

Cited by 97 publications

References 40 publications

Glucose-6-phosphate dehydrogenase blockade potentiates tyrosine kinase inhibitor effect on breast cancer cells through autophagy perturbation

Glucose-6-phosphate dehydrogenase blockade potentiates tyrosine kinase inhibitor effect on breast cancer cells through autophagy perturbation

Natural Polyphenols Targeting Senescence: A Novel Prevention and Therapy Strategy for Cancer

Nitidine Chloride Is a Potential Alternative Therapy for Glioma Through Inducing Endoplasmic Reticulum Stress and Alleviating Epithelial-Mesenchymal Transition

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