Overactivated NRF2 induces pseudohypoxia in hepatocellular carcinoma by stabilizing HIF-1α

Zheng, Jun; Kim, Su-Jung; Saeidi, Soma; Kim, Seong Hoon; Fang, Xizhu; Lee, Yeon‐Hwa; Quispe, Yanymee N. Guillen; Ngo, Hoang Kieu Chi; Kim, Do-Hee; Kim, Doojin; Surh, Young‐Joon

doi:10.1016/j.freeradbiomed.2022.11.039

Cited by 14 publications

(9 citation statements)

References 44 publications

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“…In combination with increased cancer cell motility through EMT, angiogenesis, a critical feature that enhances dissemination of metastatic cancer cells, is increased by NRF2 ( Huang et al, 2021 ; Liu et al, 2021 ; Shahcheraghi et al, 2022 ). This increased angiogenesis has been attributed to NRF2-mediated stabilization of HIF-1α and activation of its transcriptional program ( Ji et al, 2014 ; Zheng et al, 2023 ). Finally, there is a connection between mitochondrial stress and NRF2.…”

Section: Metastasismentioning

confidence: 99%

The Multi-Faceted Consequences of NRF2 Activation throughout Carcinogenesis

Occhiuto

Moerland

Leal

et al. 2023

Molecules and Cells

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The oxidative balance of a cell is maintained by the Kelch-like ECH-associated protein 1 (KEAP1)/nuclear factor erythroid 2-related factor 2 (NRF2) pathway. This cytoprotective pathway detoxifies reactive oxygen species and xenobiotics. The role of the KEAP1/NRF2 pathway as pro-tumorigenic or anti-tumorigenic throughout stages of carcinogenesis (including initiation, promotion, progression, and metastasis) is complex. This mini review focuses on key studies describing how the KEAP1/NRF2 pathway affects cancer at different phases. The data compiled suggest that the roles of KEAP1/NRF2 in cancer are highly dependent on context; specifically, the model used (carcinogen-induced vs genetic), the tumor type, and the stage of cancer. Moreover, emerging data suggests that KEAP1/NRF2 is also important for regulating the tumor microenvironment and how its effects are amplified either by epigenetics or in response to co-occurring mutations. Further elucidation of the complexity of this pathway is needed in order to develop novel pharmacological tools and drugs to improve patient outcomes.

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Section: Metastasismentioning

confidence: 99%

The Multi-Faceted Consequences of NRF2 Activation throughout Carcinogenesis

Occhiuto

Moerland

Leal

et al. 2023

Molecules and Cells

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“…86 Actually, overexpression of Nrf2, which could occur during the ozone therapy, generates a “pseudo-hypoxia”, leading to a delay in the HIF-1α proteolysis, as Nrf2 tends to stabilize the existence of HIF-1α. 85 Ozone induces NO from endothelia and a close cross talk between HIF-1α and NO was reported elsewhere. 87,88 NO should inhibit HIF-1α but the ongoing existence of ROS lowers this ability, leaving the pseudo-hypoxic stimulus to work as a promotion of the microvasculature function.…”

Section: Introductionmentioning

confidence: 56%

“…84 The precise interplay and regulatory mechanisms between HIF-1α and Nrf2 are complex and context-dependent, and more research is needed to fully understand their relationship. 85 Nevertheless, their cooperative or competitive interactions contribute to the overall cellular response to stress, promoting cell survival and maintaining redox homeostasis in various physiological and pathological conditions. The interplay HIF-1α/Nrf2 causes the release of nitric oxide (NO) from endothelia, one of the numerous effects of ozone pre-conditioning, acting on experimental ischemia/ reperfusion (I/R) injury.…”

Section: Ozone Oxygen and The Microcirculationmentioning

confidence: 99%

Ozone in the adjunct medical treatment. The round personality of a molecule with hormetic properties

Chirumbolo,

Tirelli,

Franzini

et al. 2023

Hum Exp Toxicol

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Ozone, an allotrope of oxygen, is enjoying an increasing interest in the setting and management of the medical adjunct treatment, which is called, maybe too simplistically, “ozone therapy”. Ozone is not a medicine, so the word therapy does not properly fit this gaseous molecule. Like many natural compounds, for example plant flavonoids, even ozone interacts with aryl hydrocarbon receptors (AhRs) and, at low doses, it works according to the paradoxical mechanism of hormesis, involving mitochondria (mitohormesis). Ozone, in the hormetic range, exerts cell protective functions via the Nrf2-mediated activation of the anti-oxidant system, then leading to anti-inflammatory effects, also via the triggering of low doses of 4-HNE. Moreover, its interaction with plasma and lipids forms reactive oxygen species (ROS) and lipoperoxides (LPOs), generally called ozonides, which are enabled to rule the major molecular actions of ozone in the cell. Ozone behaves as a bioregulator, by activating a wide population of reactive intermediates, which usually target mitochondria and their turnover/biogenesis, often leading to a pleiotropic spectrum of actions and behaving as a tuner of the fundamental mechanisms of survival in the cell. In this sense, ozone can be considered a novelty in the medical sciences and in the clinical approach to pharmacology and medical therapy, due to its ability to target complex regulatory systems and not simple receptors.

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“…A recent study in cultured HCC cells found that Nrf2 directly binds to the oxygen dependent degradation (ODD) domain of HIF-1α, which limits prolyl hydroxylase domain proteins (PHDs) mediated hydroxylation of HIF-1α, thereby preventing binding of hydroxylated HIF-1α to von-Hippel-Lindau (VHL) for proteasomal degradation, which represents breaking NRF2-HIF-1α alliance may provide more efficient therapeutic strategies than targeting each transcription factor alone. 42 After the administration of chemotherapy, the Bcl-2/BAX ratio determines whether tumor cells are sensitive to apoptosis. 43,44 In the study, treatment with As…”

Section: Discussionmentioning

confidence: 99%

Nrf2-siRNA Enhanced the Anti-Tumor Effects of As2O3 in 5-Fluorouracil-Resistant Hepatocellular Carcinoma by Inhibiting HIF-1α/HSP70 Signaling

Duan¹,

Xu²,

Li³

et al. 2022

JHC

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Chemoresistance is a major factor contributing to the failure of cancer treatment. The conventional chemotherapy agent 5-fluorouracil (5-FU) has been used for cancer treatment for decades. However, its use is limited in the treatment of hepatocellular carcinoma (HCC) due to acquired resistance. Nrf2 (NF-E2-related factor 2) is known to be associated with drug resistance across a wide range of cancer types. Also, since arsenic trioxide (As 2 O 3 ) showed antitumor effects on HCC, the purpose of this study was to determine whether As 2 O 3 and Nrf2-siRNA could inhibit HCC synergistically. Methods: We generated two separate 5-FU-resistant HCC cell lines (SNU-387/5-FU and Hep3B/5-FU). Western blotting was used to determine protein levels. An efficient lentiviral delivery system was used to establish stable knockdown or overexpression of Nrf2 and HIF-1α. In vitro and in vivo analyses of the effects of Nrf2 gene knockdown and As 2 O 3 on 5-FU-resistant HCC cells were conducted. Results: The expression of Nrf2 was higher in the 5-FU-resistant HCC cell lines than in the parental cell lines. When coupled with Nrf2 knockdown, As 2 O 3 treatment significantly decreased 5-FU-resistant SNU-387 and Hep3B cell viability, migration, and invasion, inactivated HIF-1α/HSP70 signaling, inhibited anti-apoptotic B-cell lymphoma (Bcl-2) activity, and increased the expression of proapoptotic Bcl-2-associated X protein (BAX) along with caspase-3. The synergistic effect was also confirmed using a 5-FU-resistant Hep3B mouse xenograft model in vivo. Conclusion: Nrf2 knockdown could improve the effect of As 2 O 3 on reversing drug resistance in 5-FU-resistant HCC cells.

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Overactivated NRF2 induces pseudohypoxia in hepatocellular carcinoma by stabilizing HIF-1α

Cited by 14 publications

References 44 publications

The Multi-Faceted Consequences of NRF2 Activation throughout Carcinogenesis

The Multi-Faceted Consequences of NRF2 Activation throughout Carcinogenesis

Ozone in the adjunct medical treatment. The round personality of a molecule with hormetic properties

Nrf2-siRNA Enhanced the Anti-Tumor Effects of As2O3 in 5-Fluorouracil-Resistant Hepatocellular Carcinoma by Inhibiting HIF-1α/HSP70 Signaling

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