Beclin-1-mediated Autophagy Protects Against Cadmium-activated Apoptosis via the Fas/FasL Pathway in Primary Rat Proximal Tubular Cell Culture

Liu, Gang; Yuan, Yan; Long, Manmei; Luo, Tongwang; Bian, Jianchun; Gu, Jianhong; Zou, Hui; Song, Ruilong; Wang, Yi; Wang, Lin; Liu, Zongping

doi:10.1038/s41598-017-00997-w

Cited by 45 publications

(22 citation statements)

References 45 publications

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“…Beclin-1 is a key gene participating in the initial process of autophagy (48). The expression of Beclin-1 was promoted after sorafenib treatment in the present study.…”

Section: Discussionsupporting

confidence: 63%

Inhibition of autophagy enhances the targeted therapeutic effect of sorafenib in thyroid cancer

et al. 2017

Oncol Rep

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The multi-target kinase inhibitor sorafenib has been approved for the treatment of patients with advanced differentiated thyroid cancer. However, different sensitivities to sorafenib have been observed, and few patients have benefited from sorafenib treatment in the long term. In the event of acquired resistance to sorafenib it is not beneficial to continue treatment in most patients. Autophagy can be induced in a variety of cancer treatments and plays an important role in cancer treatment. The role of autophagy in sorafenib treatment of thyroid cancer has not been fully demonstrated. The present study investigated whether autophagy is activated by sorafenib during the treatment of thyroid cancer, examined the underlying mechanisms, and explored potential strategies to enhance the therapeutic sensitivity of sorafenib. Chloroquine (CQ) is an autophagy inhibitor that has been reported to increase sensitivity to various cancer treatments. Thyroid cancer xenograft model mice were treated with sorafenib, CQ, or a combination of sorafenib and CQ. We observed that CQ or sorafenib treatment suppressed tumor growth, while mice treated with the combination of sorafenib and CQ displayed significantly reduced tumor growth compared with those treated with sorafenib or CQ alone. Western blotting results indicated that sorafenib concurrently inhibited the activities of the MAPK and AKT/mTOR pathways in thyroid cancer. Autophagy was activated by sorafenib in thyroid cancer, both in vitro and in vivo, which was at least in part due to suppression of the AKT/mTOR pathway. Combination treatment including CQ could inhibit the autophagic flux induced by sorafenib. Silencing the key autophagy gene ATG5 using small interfering RNA also increased the anticancer effect of sorafenib. In summary, the present study revealed that inhibition of autophagy enhances the anticancer effect of sorafenib, and the combination of CQ with sorafenib treatment represents a potential therapeutic strategy for treating advanced differentiated thyroid cancer.

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“…Beclin-1 is a key gene participating in the initial process of autophagy (48). The expression of Beclin-1 was promoted after sorafenib treatment in the present study.…”

Section: Discussionsupporting

confidence: 63%

Inhibition of autophagy enhances the targeted therapeutic effect of sorafenib in thyroid cancer

et al. 2017

Oncol Rep

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“…Beclin 1 interacts with Bcl-2 under normal circumstances and its activity is limited by Bcl-2. Activated autophagy with upregulated Beclin 1 was found when Bcl-2 was silenced by siRNA in epithelial cells [49,50,51]. Our data indicated that continuous incubation with T-2 toxin led to the downregulation of Beclin 1 and Bcl-2 levels with the cleavage of caspase-3, suggesting that autophagy and apoptosis are interactive and excessively activated apoptosis can in fact inhibit autophagy by disabling Beclin 1 through caspase cleavage.…”

Section: Discussionmentioning

confidence: 67%

Autophagy and Apoptosis Interact to Modulate T-2 Toxin-Induced Toxicity in Liver Cells

Zhou

Yuan

et al. 2019

Toxins

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T-2 toxin is a mycotoxin generated by Fusarium species which has been shown to be highly toxic to human and animals. T-2 toxin induces apoptosis in various tissues/organs. Apoptosis and autophagy are two closely interconnected processes, which are important for maintaining physiological homeostasis as well as pathogenesis. Here, for the first time, we demonstrated that T-2 toxins induce autophagy in human liver cells (L02). We demonstrated that T-2 toxin induce acidic vesicular organelles formation, concomitant with the alterations in p62/SQSTM1 and LC3-phosphatidylethanolamine conjugate (LC3-II) and the enhancement of the autophagic flux. Using mRFP-GFP-LC3 by lentiviral transduction, we showed T-2 toxin-mediated lysosomal fusion and the formation of autophagosomes in L02 cells. The formation of autophagosomes was further confirmed by transmission electron microcopy. While T-2 toxin induced both autophagy and apoptosis, autophagy appears to be a leading event in the response to T-2 toxin treatment, reflecting its protective role in cells against cellular damage. Activating autophagy by rapamycin (RAPA) inhibited apoptosis, while suppressing autophagy by chloroquine greatly enhanced the T-2 toxin-induced apoptosis, suggesting the crosstalk between autophagy and apoptosis. Taken together, these results indicate that autophagy plays a role in protecting cells from T-2 toxin-induced apoptosis suggesting that autophagy may be manipulated for the alleviation of toxic responses induced by T-2 toxin.

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“…It has been demonstrated that Cd exposure can induce cell apoptosis by activating the Fas/FasL pathway in hepatoma cells 28 . Our previous study showed that Cd induces activation of the Fas/FasL apoptosis pathway in rat proximal tubular cells 29 . However, involvement of the Fas/FasL signaling pathway in neuronal apoptosis induced by Cd is still unclear.…”

Section: Discussionmentioning

confidence: 96%

Cadmium-induced apoptosis in neuronal cells is mediated by Fas/FasL-mediated mitochondrial apoptotic signaling pathway

Yuan

Zhang

Zhao

et al. 2018

Sci Rep

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Cadmium (Cd) is a toxic metal capable of damaging brain. Studies have demonstrated that Cd can induce apoptosis in neuronal cells. The CD95/APO-1 (Fas)/Fas Ligand (FasL) signaling pathway is one of the primary apoptosis pathways, but the role and regulatory mechanism of this pathway in neuronal cells remain unclear. Here, we demonstrated the underlying mechanism of the Fas/FasL system involving the mitochondrial apoptotic pathway in neuronal cells. Primary rat cerebral cortical neurons and PC12 cells were exposed to Cd, which significantly activated expression of Fas, FasL, Fas-associated death domain (FADD) and cleaved caspase-8. However, expression of cleaved caspase-8 decreased at 20 µM Cd in primary cerebral cortical neurons. Importantly, Cd-induced apoptotic morphological changes and increase in the apoptosis rate were partially blocked by Z-IETD-FMK, which is a specific inhibitor of caspase-8. Cd-mediated increase of apoptosis rate was inhibited by anti-FasL antibody. Furthermore, our data revealed that Z-IETD-FMK also blocked increase of truncated BH3 interacting domain death agonist (tBID)/BID, decrease of the B-cell lymphoma 2 (Bcl-2)/Bcl-2 associate X protein (Bax) ratio and mitochondrial membrane potential (MMP), release of cytochrome c, as well as cleavage of caspase-9/3 and poly (ADP-ribose) polymerase (PARP) induced by Cd. Taken together, our results demonstrate that the Fas/FasL-mediated mitochondrial apoptotic pathway plays an important role in Cd-induced neuronal apoptosis.

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Beclin-1-mediated Autophagy Protects Against Cadmium-activated Apoptosis via the Fas/FasL Pathway in Primary Rat Proximal Tubular Cell Culture

Cited by 45 publications

References 45 publications

Inhibition of autophagy enhances the targeted therapeutic effect of sorafenib in thyroid cancer

Inhibition of autophagy enhances the targeted therapeutic effect of sorafenib in thyroid cancer

Autophagy and Apoptosis Interact to Modulate T-2 Toxin-Induced Toxicity in Liver Cells

Cadmium-induced apoptosis in neuronal cells is mediated by Fas/FasL-mediated mitochondrial apoptotic signaling pathway

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