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Review
. 2020 Aug 5;12(8):2185.
doi: 10.3390/cancers12082185.

The Role of Necroptosis in ROS-Mediated Cancer Therapies and Its Promising Applications

Sheng-Kai Hsu  1   2 , Wen-Tsan Chang  3   4   5 , I-Ling Lin  2   6 , Yih-Fung Chen  7 , Nitin Balkrushna Padalwar  8 , Kai-Chun Cheng  9   10 , Yen-Ni Teng  11 , Chi-Huei Wang  1 , Chien-Chih Chiu  1   5   12   13   14
Affiliations
Review

"VSports app下载" The Role of Necroptosis in ROS-Mediated Cancer Therapies and Its Promising Applications

Sheng-Kai Hsu et al. Cancers (Basel). .

Abstract

Over the past decades, promising therapies targeting different signaling pathways have emerged. Among these pathways, apoptosis has been well investigated and targeted to design diverse chemotherapies. However, some patients are chemoresistant to these therapies due to compromised apoptotic cell death. Hence, exploring alternative treatments aimed at different mechanisms of cell death seems to be a potential strategy for bypassing impaired apoptotic cell death VSports手机版. Emerging evidence has shown that necroptosis, a caspase-independent form of cell death with features between apoptosis and necrosis, can overcome the predicament of drug resistance. Furthermore, previous studies have also indicated that there is a close correlation between necroptosis and reactive oxygen species (ROS); both necroptosis and ROS play significant roles both under human physiological conditions such as the regulation of inflammation and in cancer biology. Several small molecules used in experiments and clinical practice eliminate cancer cells via the modulation of ROS and necroptosis. The molecular mechanisms of these promising therapies are discussed in detail in this review. .

Keywords: cancer; chemotherapy; necroptosis; reactive oxygen species. V体育安卓版.

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Conflict of interest statement

The authors report no conflicts of interest.

Figures

Figure 1
Figure 1
Reactive oxygen species (ROS) generation and modulation of cell signaling events. The four mitochondrial complexes embedded in the mitochondrial inner membrane—complexes I, II, III and IV—are responsible for electron transfer. ROS can be generated by complexes I, II and III. ROS produced by complexes I and II are primarily located in the matrix, while complex III can generate O2• in both the intermembrane space and matrix. Nevertheless, intermembrane ROS translocate to the cytosol and cellular trigger events; ROS can stabilize HIFα under hypoxic conditions, and this stabilization subsequently induces VEGF expression to promote endothelial cell proliferation and angiogenesis. ROS can also initiate the ERK signaling pathway, promoting cell proliferation and survival and anchorage-independent growth. Moreover, they can lead to genomic instability and induce cancer progression.
Figure 2
Figure 2
Overview of the cell death receptor-associated signaling pathway. The signaling pathway is initiated by the interaction between the TNFR superfamily members and their ligands. (a) TNF-α binds with TNFR1, which recruits TRADD, TRAF2, CYLD, cIAP1, cIAP2 and RIP1 to form complex I. If cIAP1 polyubiquitinates RIP1, complex I activates both the NF-κB and MAPK signaling pathways. However, if RIP1 is deubiquitinated by CYLD, complex IIa or complex IIb may be subsequently formed to induce apoptosis or necroptosis, respectively. When caspase-8 is intact, the formation of complex II, which leads to apoptosis and RIP3 inhibition, is favored. Conversely, if caspase-8 is compromised, the formation of complex IIb (known as the necrosome), which consists of RIP1, RIP3 and FADD, is inclined to phosphorylate MLKL, leading to necroptosis via the translocation of phosphorylated MLKL and plasma membrane permeabilization. (b) Fas ligand (CD95L) binds with Fas receptor (CD95); this recruits FADD, procaspase-8 and cFLIP to form DISC. Similarly, intact caspase-8 favors the formation of complex IIa and apoptosis. However, inactive caspase-8 contributes to the formation of complex IIb and necroptosis. (c) The interaction between TRAIL and DR4/5 leads to the apoptotic and necroptotic situations mentioned above, based on the activity of caspase-8. (d) In the presence of genotoxic stresses, the removal of IAP or anti-tumor drugs (e.g., etoposide), RIP1 is activated to form the ripotosome, which consists of RIP1, RIP3, FADD, procaspase-8 and cFLIPL. If cFLIPs is present, the phosphorylation of MLKL by the ripotosome is inhibited, and apoptosis is favored. By contrast, the absence of cFLIPs leads to the phosphorylation of MLKL, which favors necroptosis. The figure was redrawn and modified from [2].
Figure 3
Figure 3
The crosstalk between ROS and necroptosis. ROS and necroptosis can form a positive feedback loop. Extramitochondrial ROS production by NOX1 or mitochondrial ROS generation through oxidative phosphorylation modifies the C257, C268 and C586 residues of RIP1 and facilitates the autophosphorylation of RIP1 at S161. This leads to the recruitment of RIP3 and necroptosis [81,82]. RIP1 can induce ROS production by inhibiting adenine-nucleotide translocase (ANT) and increasing ATP [83]. RIP3 can induce ROS generation through metabolic signaling pathways: (a) Upregulation of PYGL promotes the expression of PDH, which increases TCA cycle activity to induce aerobic respiration and produce ROS [84]. (b) Elevation of GLUL upregulates GLUD1 and increases glutaminolysis, further facilitating the TCA cycle and aerobic respiration. Furthermore, RIP1- and RIP3-mediated ROS production can reactivate necroptosis, forming a positive feedback loop [78,85].
Figure 4
Figure 4
The potential drugs and their targets in modulation of necroptosis and ROS.
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References

    1. Kaufmann S.H., Earnshaw W.C. Induction of apoptosis by cancer chemotherapy. Exp. Cell Res. 2000;256:42–49. doi: 10.1006/excr.2000.4838. - DOI - PubMed
    1. Su Z., Yang Z., Xie L., DeWitt J.P., Chen Y. Cancer therapy in the necroptosis era. Cell Death Differ. 2016;23:748–756. doi: 10.1038/cdd.2016.8. - DOI (VSports) - PMC - PubMed
    1. Sethi G., Shanmugam M.K., Warrier S., Merarchi M., Arfuso F., Kumar A.P., Bishayee A. Pro-Apoptotic and Anti-Cancer Properties of Diosgenin: A Comprehensive and Critical Review. Nutrients. 2018;10:645. doi: 10.3390/nu10050645. - "V体育平台登录" DOI - PMC - PubMed
    1. Li Y., Wang X., Cheng S., Du J., Deng Z., Zhang Y., Liu Q., Gao J., Cheng B., Ling C. Diosgenin induces G2/M cell cycle arrest and apoptosis in human hepatocellular carcinoma cells. Oncol. Rep. 2015;33:693–698. doi: 10.3892/or.2014.3629. - DOI (V体育官网) - PubMed
    1. Srinivasan S., Koduru S., Kumar R., Venguswamy G., Kyprianou N., Damodaran C. Diosgenin targets Akt-mediated prosurvival signaling in human breast cancer cells. Int. J. Cancer. 2009;125:961–967. doi: 10.1002/ijc.24419. - "V体育ios版" DOI - PubMed

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