The expression and regulation of DFNA5 in human hepatocellular carcinoma DFNA5 in hepatocellular carcinoma

Wang, Congjun; Tang, Lin; Shen, Dayong; Wang, Chao; Yuan, Qiong‐Ying; Gao, Wei; Wang, Yongkun; Xu, Ru; Zhang, Hui

doi:10.1007/s11033-013-2581-8

Cited by 78 publications

(55 citation statements)

References 30 publications

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“…High GSDME expression could guide cells to pyroptosis before the onset of apoptosis. 18 Although GSDME is not expressed in many types of cancer cells, 18 , 52 – 54 GSDME is specifically and highly expressed in melanoma tissues 55 and melanoma cell lines. This high GSDME expression may serve as an Achilles’ heel for melanoma, providing an opportunity for melanoma therapy via pyroptosis induction.…”

Section: Discussionmentioning

confidence: 99%

Tom20 senses iron-activated ROS signaling to promote melanoma cell pyroptosis

et al. 2018

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Iron has been shown to trigger oxidative stress by elevating reactive oxygen species (ROS) and to participate in different modes of cell death, such as ferroptosis, apoptosis and necroptosis. However, whether iron-elevated ROS is also linked to pyroptosis has not been reported. Here, we demonstrate that iron-activated ROS can induce pyroptosis via a Tom20-Bax-caspase-GSDME pathway. In melanoma cells, iron enhanced ROS signaling initiated by CCCP, causing the oxidation and oligomerization of the mitochondrial outer membrane protein Tom20. Bax is recruited to mitochondria by oxidized Tom20, which facilitates cytochrome c release to cytosol to activate caspase-3, eventually triggering pyroptotic death by inducing GSDME cleavage. Therefore, ROS acts as a causative factor and Tom20 senses ROS signaling for iron-driven pyroptotic death of melanoma cells. Since iron activates ROS for GSDME-dependent pyroptosis induction and melanoma cells specifically express a high level of GSDME, iron may be a potential candidate for melanoma therapy. Based on the functional mechanism of iron shown above, we further demonstrate that iron supplementation at a dosage used in iron-deficient patients is sufficient to maximize the anti-tumor effect of clinical ROS-inducing drugs to inhibit xenograft tumor growth and metastasis of melanoma cells through GSDME-dependent pyroptosis. Moreover, no obvious side effects are observed in the normal tissues and organs of mice during the combined treatment of clinical drugs and iron. This study not only identifies iron as a sensitizer amplifying ROS signaling to drive pyroptosis, but also implicates a novel iron-based intervention strategy for melanoma therapy.

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Section: Discussionmentioning

confidence: 99%

Tom20 senses iron-activated ROS signaling to promote melanoma cell pyroptosis

et al. 2018

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“…Hence, it is considered as a tumor suppressor. 42, 43, 44, 45 The precise physiological function of the DFNA5 correlated to its tumor suppressive characteristics remains to be elucidated. On the other hand, various functional studies hinted that DFNA5 harbors a proapoptotic function.…”

Section: Dfna5 Is Implicated In An Apoptotic Pathwaymentioning

confidence: 99%

‘Hints’ in the killer protein gasdermin D: unveiling the secrets of gasdermins driving cell death

2017

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Pyroptosis is a lytic form of cell death distinguished from apoptosis, ferroptosis, necrosis, necroptosis, NETosis, oncosis, pyronecrosis and autophagy. Proinflammatory caspases cleave a gasdermin D (GSDMD) protein to generate a 31 kDa N-terminal domain. The cleavage relieves the intramolecular inhibition on the gasdermin-N domain, which then moves to the plasma membrane to exhibit pore-forming activity. Thus, GSDMD acts as the final and direct executor of pyroptotic cell death. Owing to the selective targeting of the inner leaflet of the plasma membrane with the pore-forming that determines pyroptotic cell death, GSDMD could be a potential target to control cell death or extracellular bacterial infections. Intriguingly, other gasdermin family members also share similar N-terminal domains, but they present different cell death programs. Herein, we summarize features and functions of the novel player proteins in cell death, including GSDMD triggering pyroptosis, Gsdma3/GSDMA initiating autophagy/ apoptosis and DFNA5 inducing apoptosis/secondary necrosis. The gasdermin N terminus appears to be a novel pore-forming protein. This provides novel insight into the underlying roles and mechanisms of lytic or nonlytic forms of programmed cell death, as well as their potential applications in inflammation-associated diseases.

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“…Endogenous DFNA5 is epigenetically silenced by hypermethylation in cancer cells resulting in a decreased DFNA5 expression level. Based on these findings, it is hypothesized that DFNA5 is a tumor suppressor gene (TSG) (Akino et al, 2007 ; Kim et al, 2008a , b ; Wang et al, 2013 ).…”

Section: Introductionmentioning

confidence: 99%

The deafness gene DFNA5 induces programmed cell death through mitochondria and MAPK-related pathways

Rossom

Beeck

Hristovska

et al. 2015

Front. Cell. Neurosci.

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Cell death exists in many different forms. Some are accidental, but most of them have some kind of regulation and are called programmed cell death. Programmed cell death (PCD) is a very diverse and complex mechanism and must be tightly regulated. This study investigated PCD induced by DFNA5, a gene responsible for autosomal dominant hearing loss (HL) and a tumor suppressor gene (TSG) involved in frequent forms of cancer. Mutations in DFNA5 lead to exon 8 skipping and result in HL in several families. Expression of mutant DFNA5, a cDNA construct where exon 8 is deleted, was linked to PCD both in human cell lines and in Saccharomyces cerevisiae. To further investigate the cell death mechanism induced by mutant DFNA5, we performed a microarray study in both models. We used wild-type DFNA5, which does not induce cell death, as a reference. Our data showed that the yeast pathways related to mitochondrial ATP-coupled electron transport chain, oxidative phosphorylation and energy metabolism were up-regulated, while in human cell lines, MAP kinase-related activity was up-regulated. Inhibition of this pathway was able to partially attenuate the resulting cell death induced by mutant DFNA5 in human cell lines. In yeast, the association with mitochondria was demonstrated by up-regulation of several cytochrome c oxidase (COX) genes involved in the cellular oxidative stress production. Both models show a down-regulation of protein sorting- and folding-related mechanisms suggesting an additional role for the endoplasmic reticulum (ER). The exact relationship between ER and mitochondria in DFNA5-induced cell death remains unknown at this moment, but these results suggest a potential link between the two.

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The expression and regulation of DFNA5 in human hepatocellular carcinoma DFNA5 in hepatocellular carcinoma

Cited by 78 publications

References 30 publications

Tom20 senses iron-activated ROS signaling to promote melanoma cell pyroptosis

Tom20 senses iron-activated ROS signaling to promote melanoma cell pyroptosis

‘Hints’ in the killer protein gasdermin D: unveiling the secrets of gasdermins driving cell death

The deafness gene DFNA5 induces programmed cell death through mitochondria and MAPK-related pathways

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