Nedd4 ubiquitylates VDAC2/3 to suppress erastin-induced ferroptosis in melanoma

Yang, Yongfei; Luo, Meiying; Zhang, Kexin; Zhang, Jun; Gao, Ting; Connell, Douglas O’; Yao, Fengping; Mu, Changwen; Cai, Bingyu; Shang, Yuxue; Chen, Wei

doi:10.1038/s41467-020-14324-x

Cited by 318 publications

(233 citation statements)

References 29 publications

Supporting

Mentioning

226

Contrasting

Order By: Relevance

“…Nevertheless, both the lipid peroxidation inhibitor ferrostatin-1 and the iron-chelating reagent deferiprone alleviated TalaA-induced cell death, showing that ferroptosis is the main mechanism by which TalaA induces cell death. It is noteworthy that the capability of TalaA to induce ferroptosis is stronger than that of erastin, a well-known specific ferroptosis inducer 36 . Moreover, IC 50 of TalaA was much lower than that of erastin in CRC cells, indicating that TalaA would have greater potential as a therapeutic agent in cancer treatment than erastin.…”

Section: Discussionmentioning

confidence: 95%

Discovery of a novel ferroptosis inducer-talaroconvolutin A—killing colorectal cancer cells in vitro and in vivo

Xia

Liu

et al. 2020

Cell Death Dis

View full text Add to dashboard Cite

Ferropotsis is among the most important mechanisms of cancer suppression, which could be harnessed for cancer therapy. However, no natural small-molecule compounds with cancer inhibitory activity have been identified to date. In the present study, we reported the discovery of a novel ferroptosis inducer, talaroconvolutin A (TalaA), and the underlying molecular mechanism. We discovered that TalaA killed colorectal cancer cells in dose-dependent and time-dependent manners. Interestingly, TalaA did not induce apoptosis, but strongly triggered ferroptosis. Notably, TalaA was significantly more effective than erastin (a well-known ferroptosis inducer) in suppressing colorectal cancer cells via ferroptosis. We revealed a dual mechanism of TalaA’ action against cancer. On the one hand, TalaA considerably increased reactive oxygen species levels to a certain threshold, the exceeding of which induced ferroptosis. On the other hand, this compound downregulated the expression of the channel protein solute carrier family 7 member 11 (SLC7A11) but upregulated arachidonate lipoxygenase 3 (ALOXE3), promoting ferroptosis. Furthermore, in vivo experiments in mice evidenced that TalaA effectively suppressed the growth of xenografted colorectal cancer cells without obvious liver and kidney toxicities. The findings of this study indicated that TalaA could be a new potential powerful drug candidate for colorectal cancer therapy due to its outstanding ability to kill colorectal cancer cells via ferroptosis induction.

show abstract

Section: Discussionmentioning

confidence: 95%

Discovery of a novel ferroptosis inducer-talaroconvolutin A—killing colorectal cancer cells in vitro and in vivo

Xia

Liu

et al. 2020

Cell Death Dis

View full text Add to dashboard Cite

show abstract

“…NEDD4-dependent VDAC2/3 degradation and NEDD4L-mediated LTF degradation act as a feedback mechanism to limit ferroptosis in cancer cells. 41,75 ZFP36 ring finger protein (ZFP36/TTP) is an RNA-binding protein and negative regulator of ferroptosis in hepatic stellate cells. 124 Fbox and WD repeat domain-containing 7 (FBXW7/CDC4)-mediated ZFP36 degradation inhibits autophagy-dependent ferroptosis by destabilizing ATG16L1 mRNA, 124 providing an example for studying the role of proteasome-dependent degradation of epigenetic regulators in autophagy-dependent ferroptosis.…”

Section: Upsmentioning

confidence: 99%

Ferroptosis: molecular mechanisms and health implications

et al. 2020

View full text Add to dashboard Cite

Cell death can be executed through different subroutines. Since the description of ferroptosis as an iron-dependent form of non-apoptotic cell death in 2012, there has been mounting interest in the process and function of ferroptosis. Ferroptosis can occur through two major pathways, the extrinsic or transporter-dependent pathway and the intrinsic or enzyme-regulated pathway. Ferroptosis is caused by a redox imbalance between the production of oxidants and antioxidants, which is driven by the abnormal expression and activity of multiple redox-active enzymes that produce or detoxify free radicals and lipid oxidation products. Accordingly, ferroptosis is precisely regulated at multiple levels, including epigenetic, transcriptional, posttranscriptional and posttranslational layers. The transcription factor NFE2L2 plays a central role in upregulating anti-ferroptotic defense, whereas selective autophagy may promote ferroptotic death. Here, we review current knowledge on the integrated molecular machinery of ferroptosis and describe how dysregulated ferroptosis is involved in cancer, neurodegeneration, tissue injury, inflammation, and infection.

show abstract

“…Similarly, RSL3 treatment causes VDAC2/3 degradation through Nedd4 [26]. However, knockdown of VDAC2/3 suppresses the sensitivity of cells to erastin but not to RSL3 [180].…”

Section: Ferroptosis Mediated By Mitochondrial Vdacsmentioning

confidence: 99%

Ferroptosis and Cancer: Mitochondria Meet the “Iron Maiden” Cell Death

Battaglia

Chirillo

Aversa

et al. 2020

Cells

355

232

View full text Add to dashboard Cite

Ferroptosis is a new type of oxidative regulated cell death (RCD) driven by iron-dependent lipid peroxidation. As major sites of iron utilization and master regulators of oxidative metabolism, mitochondria are the main source of reactive oxygen species (ROS) and, thus, play a role in this type of RCD. Ferroptosis is, indeed, associated with severe damage in mitochondrial morphology, bioenergetics, and metabolism. Furthermore, dysregulation of mitochondrial metabolism is considered a biochemical feature of neurodegenerative diseases linked to ferroptosis. Whether mitochondrial dysfunction can, per se, initiate ferroptosis and whether mitochondrial function in ferroptosis is context-dependent are still under debate. Cancer cells accumulate high levels of iron and ROS to promote their metabolic activity and growth. Of note, cancer cell metabolic rewiring is often associated with acquired sensitivity to ferroptosis. This strongly suggests that ferroptosis may act as an adaptive response to metabolic imbalance and, thus, may constitute a new promising way to eradicate malignant cells. Here, we review the current literature on the role of mitochondria in ferroptosis, and we discuss opportunities to potentially use mitochondria-mediated ferroptosis as a new strategy for cancer therapy.

show abstract

Nedd4 ubiquitylates VDAC2/3 to suppress erastin-induced ferroptosis in melanoma

Cited by 318 publications

References 29 publications

Discovery of a novel ferroptosis inducer-talaroconvolutin A—killing colorectal cancer cells in vitro and in vivo

Discovery of a novel ferroptosis inducer-talaroconvolutin A—killing colorectal cancer cells in vitro and in vivo

Ferroptosis: molecular mechanisms and health implications

Ferroptosis and Cancer: Mitochondria Meet the “Iron Maiden” Cell Death

Contact Info

Product

Resources

About