Redox signaling and unfolded protein response coordinate cell fate decisions under ER stress

Zhang, Zhe; Zhang, Lu; Zhou, Li; Y, Lei; Zhang, Yuanyuan; Huang, Canhua

doi:10.1016/j.redox.2018.11.005

Cited by 280 publications

(216 citation statements)

References 157 publications

(217 reference statements)

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“…Notably, there exist multiple cross-talks between UPR-and ARE-driven signaling cascades, aiming to maintain cellular redox, protein and lipid homeostasis. Altogether, these responses can make cell fate decisions to be modulated under ER stress conditions [58], as discovered for its homologous Skn-1 in Caenorhabditis elegans [18].…”

Section: Resultsmentioning

confidence: 95%

A unity of opposites in between Nrf1- and Nrf2-mediated responses to the endoplasmic reticulum stressor tunicamycin

Zhu¹,

Hu²,

Ru³

et al. 2019

Preprint

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The water-soluble Nrf2 is accepted as a master regulator of antioxidant responses to cellular stress, it was also identified as a direct target of the endoplasmic reticulum (ER)-anchored PERK. However, the membrane-bound Nrf1 response to ER stress remains elusive. Herein, we report a unity of opposites in both Nrf1-and Nrf2-coordinated responses to the ER stressor tunicamycin (TU). The TU-inducible transcription of Nrf1 and Nrf2, as well as GCLM and HO-1, was accompanied by activation of ER stress signaling networks. The unfolded protein response (UPR) mediated by ATF6, IRE1 and PERK was significantly suppressed by Nrf1-specific knockout, but hyper-expression of Nrf2, GCLM and HO-1 was retained in Nrf1 / cells. By contrast, Nrf2 /TA cells with a genomic deletion of its transactivation domain resulted in significant decreases of GCLM, HO-1 and Nrf1; this was accompanied by partial decreases of IRE1 and ATF6, but not PERK, along with an obvious increase of ATF4. Notably, Nrf1 glycosylation and its trans-activity to mediate transcriptional expression of 26S proteasomal subunits were repressed by TU. This inhibitory effect was enhanced by Nrf1 / and Nrf2 /TA , but not by a constitutive activator caNrf2 N (that increased abundances of non-glycosylated and processed Nrf1). Furthermore, caNrf2 N also enhanced induction of PERK and IRE1 by TU, but reduced expression of ATF4 and HO-1. Such distinct roles of Nrf1 and Nrf2 are unified to maintain cell homeostasis by a series of coordinated ER-to-nuclear signaling responses to TU. Overall, Nrf1 acts in a cell-autonomous manner to determine transcription of most of UPR-target genes, albeit Nrf2 is also partially involved in this process.

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Section: Resultsmentioning

confidence: 95%

A unity of opposites in between Nrf1- and Nrf2-mediated responses to the endoplasmic reticulum stressor tunicamycin

Zhu¹,

Hu²,

Ru³

et al. 2019

Preprint

View full text Add to dashboard Cite

show abstract

“…35 Elevated ROS inducing ER-stress-mediated apoptosis has also been demonstrated in different cancers. 35,36 ER stress manifests as increased phosphorylation of eIF2α, which is required for transient downregulation of protein synthesis and selective induction of ATF4. 37 ATF4 also induces the expression of CHOP, which is involved in the initiation of cell death.…”

Section: Discussionmentioning

confidence: 99%

<p>Allylated Curcumin Analog CA6 Inhibits TrxR1 and Leads to ROS-Dependent Apoptotic Cell Death in Gastric Cancer Through Akt-FoxO3a</p>

Rajamanickam

Yan

et al. 2020

CMAR

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Background: Gastric cancer is one of the leading causes of cancer-related deaths. Allylated monocarbonyl analogs of curcumin (MACs) have been reported to selectively inhibit a broad range of human cancers including gastric cancer. However, the precise molecular mechanisms underlying the inhibitory activities of MACs are not fully known. Methods: In this study, we examined the anti-tumor activities of an allylated MAC, CA6, on gastric cancer cells and gastric cancer xenograft mouse model. The potential molecular antitumor mechanisms of CA6 were also elucidated. Results: Our data show that CA6 exhibited significant cytotoxicity in gastric cancer cells, which was seen as an induction of G2/M cell cycle arrest and apoptosis. These activities were mediated through an elaboration of ROS levels in gastric cancer cells and induction of endoplasmic reticulum stress. CA6 increased ROS levels through directly binding to and inhibiting thioredoxin reductase R1 (TrxR1). Also, CA6-generated ROS inhibited Akt and activated forkhead O3A (FoxO3a), causing cytotoxicity in gastric cancer cells. Finally, CA6 treatment dose-dependently reduced the growth of gastric cancer xenografts in tumor-bearing mice, which was associated with reduced TrxR1 activity and increased ROS in the tumor. Conclusion: In summary, our studies demonstrate that CA6 inhibited gastric cancer growth by inhibiting TrxR1 and increasing ROS, which in turn activated FoxO3a through suppressing Akt. CA6 is a potential candidate for the treatment of gastric cancer.

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“…Regulated cell deaths are frequently associated with oxidative injury and ER stress [25]. Prolonged ER stress has been shown to engage a distinct set of pro-apoptotic outputs [26].…”

Section: Discussionmentioning

confidence: 99%

Nrf2 represses ER stress-related ferroptosis in renal carcinoma cells via HO-1

Shen

Tian

et al. 2020

Preprint

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Selective-induction of regulated cell death is considered as a useful strategy for developing effective therapies against renal cell carcinoma (RCC). In this study, the role of nuclear factor-E2-related factor 2 (Nrf2) and its downstream genes in erastin-induced ferroptosis of renal carcinoma cells was investigated. Erastin induced endoplasmic reticulum (ER) stress and ferroptosis in renal carcinoma cells (786-0 and Caki-1), which was confirmed by morphological changes, increased lipid oxidation and ferroptosis inhibition. Data obtained from TCGA dataset showed that Nrf2 and heme oxygenase-1 (HO-1) were not only significantly differentially expressed between RCC and normal samples, but also associated with better survival in RCC patients. Moreover, the process of ferroptosis induced by erastin in renal carcinoma cells was accompanied by increased expression of Nrf2 and HO-1. Inhibition of Nrf2 or HO-1 expression enhanced lipid ROS accumulation and ferroptosis. Furthermore, pharmacological activation of HO-1 reversed ferroptosis-sensitizing effect of Nrf2 silencing, thereby clarifying the key role of Nrf2/HO-1 pathway in erastin-induced ferroptosis in renal carcinoma cells. In summary, we identified the role of Nrf2/HO-1 signaling pathway in the protection of renal carcinoma cells from ER stress-related ferroptosis, which indicated that targeting of Nrf2/HO-1 pathway as a viable treatment strategy for RCC. Graphical abstract (supplementary figure):Nrf2 protects against ER stress-related ferroptosis via HO-1 in renal cancer cells.Cystine/glutamate antiporter (SLC7A11) abbreviated as xCT. Mitochondria abbreviated as Mito.

show abstract

Redox signaling and unfolded protein response coordinate cell fate decisions under ER stress

Cited by 280 publications

References 157 publications

A unity of opposites in between Nrf1- and Nrf2-mediated responses to the endoplasmic reticulum stressor tunicamycin

A unity of opposites in between Nrf1- and Nrf2-mediated responses to the endoplasmic reticulum stressor tunicamycin

<p>Allylated Curcumin Analog CA6 Inhibits TrxR1 and Leads to ROS-Dependent Apoptotic Cell Death in Gastric Cancer Through Akt-FoxO3a</p>

Nrf2 represses ER stress-related ferroptosis in renal carcinoma cells via HO-1

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