Activation of the p62-Keap1-NRF2 Pathway Protects against Ferroptosis in Hepatocellular Carcinoma Cells

By Xiaofang Sun, Z. Ou, Ruochan Chen, X. Niu, De Chen, R. Kang, D. Tang. Hepatology, 2015

1,772 citations recorded by the source corpus.

Ferroptosis is a recently recognized form of regulated cell death caused by an iron‐dependent accumulation of lipid reactive oxygen species. However, the molecular mechanisms regulating ferroptosis remain obscure. Here, we report that nuclear factor erythroid 2‐related factor 2 (NRF2) plays a central role in protecting hepatocellular carcinoma (HCC) cells against ferroptosis. Upon exposure to ferroptosis‐inducing compounds (e.g., erastin, sorafenib, and buthionine sulfoximine), p62 expression prevented NRF2 degradation and enhanced subsequent NRF2 nuclear accumulation through inactivation of Kelch‐like ECH‐associated protein 1. Additionally, nuclear NRF2 interacted with transcriptional coactivator small v‐maf avian musculoaponeurotic fibrosarcoma oncogene homolog proteins such as MafG and then activated transcription of quinone oxidoreductase‐1, heme oxygenase‐1, and ferritin heavy chain‐1. Knockdown of p62, quinone oxidoreductase‐1, heme oxygenase‐1, and ferritin heavy chain‐1 by RNA interference in HCC cells promoted ferroptosis in response to erastin and sorafenib. Furthermore, genetic or pharmacologic inhibition of NRF2 expression/activity in HCC cells increased the anticancer activity of erastin and sorafenib in vitro and in tumor xenograft models. Conclusion: These findings demonstrate novel molecular mechanisms and signaling pathways of ferroptosis; the status of NRF2 is a key factor that determines the therapeutic response to ferroptosis‐targeted therapies in HCC cells. (Hepatology 2016;63:173–184)

Subfields: Molecular Biology, Pulmonary and Respiratory Medicine

View Paper: https://www.semanticscholar.org/paper/8083cb25d1494ad9734d055715b0b8a351403c82

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Citations in the corpus

The molecular machinery of regulated cell death (2019, background): “NFE2L2-mediated transactivation of metallothionein 1G (MT1G, a cysteine-rich protein with a high affinity for divalent heavy metal ions), SLC7A11, and heme oxygenase 1 (HMOX1) limits ferroptosis.(143,147,148) However, upon excessive activation of NRF2, HMOX1 gets hyperactivated and induces ferroptos”
NRF2 plays a critical role in mitigating lipid peroxidation and ferroptosis (2019, background): “Indeed, treatment with trigonelline has been shown to enhance sorafenib-induced hepatocellular carcinoma cell death [57] and artesunate-induced ferroptosis in head and neck cancer cell lines [58].”
The interaction between ferroptosis and lipid metabolism in cancer (2020, background): “Moreover, Nrf2 inhibition can sensitize HN3R cells to RSL3.”
Molecular mechanisms of cell death: recommendations of the Nomenclature Committee on Cell Death 2018 (2018, background): “diphosphate farnesyltransferase 1 (FDFT1; best known as SQS) [545]; (2) the transsulfuration pathway enzyme cysteinyl-tRNA synthetase (CARS) [578]; (3) heat shock protein family B (small) member 1 (HSPB1; best known as HSP27) [579] and heat shock protein family A (Hsp70) member 5 (HSPA5) [580]; (4) ”
The Development of the Concept of Ferroptosis (2018, positive): “Year Main finding Ref 2003 Erastin was discovered through a synthetic lethal high-throughput screen to selectively kill engineered tumorigenic cells in a non-apoptotic manner [108] 2007 Erastin treatment causes the appearance of oxidative species [111] Erastin-induced cell death is inhibited by lipo”
Regulated cell death (RCD) in cancer: key pathways and targeted therapies (2022, background): “P62-keap1-nrf2 pathway plays an important role in protecting HCC cells from ferroptosis by upregulating ROS-related genes.(477) Alkaloid trigonelline reverses drug resistance by inhibiting Nrf2 in vitro and tumor xenotransplantation model, thus increasing the anti HCC activity of erastin and sorafen”
Ferroptosis: Death by Lipid Peroxidation. (2016, background): “Consistent with this hypothesis is the report that NRF2 protects against ferroptosis in hepatocellular carcinoma cells [74].”
Ferroptosis, a new form of cell death, and its relationships with tumourous diseases (2016, background): “Therefore, ferroptosis could be a new strategy for HCC treatment, and the above-discussed NRF2 and RB protein could be important treatment targets in the future.”
The Tumor Suppressor p53 Limits Ferroptosis by Blocking DPP4 Activity. (2017, neutral): “…of a variety of cancers, especially kidney cancer (Yang et al., 2014), leukemia (Yang et al., 2014; Yu et al., 2015), hepatocellular carcinoma (Louandre et al., 2013; Louandre et al., 2015; Sun et al., 2016a, 2016b), and pancreatic cancer (Eling et al., 2015; Hou et al., 2016; Zhu et al., 2017).”