Proteome analysis of NRF2 inhibition in melanoma reveals CD44 up‐regulation and increased apoptosis resistance upon vemurafenib treatment

Weitzenböck, Hans Peter; Gschwendtner, Anna; Wiesner, Christoph; Depke, Maren; Schmidt, Frank; Trautinger, Franz; Hengstschläger, Markus; Hundsberger, Harald; Mikula, Mario

doi:10.1002/cam4.4506

Cited by 10 publications

(10 citation statements)

References 37 publications

(36 reference statements)

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“…The role of Nrf2 in EMT has raised researchers’ interest in the past years but studies demonstrate contradictory results. Some studies have demonstrated that Nrf2 activation is associated with EMT induction [ 21 , 45 , 46 ] while others, as our results suggest, demonstrate that Nrf2 impairment leads to the induction of the EMT program [ 47 , 48 , 49 ] or, in the same way, that Nrf2 activation is associated with EMT inhibition [ 50 , 51 , 52 ]. Interestingly, it has also been described that Nrf2 may act as a phenotypic stability factor in restricting complete EMT by maintaining the cells in a hybrid epithelial/mesenchymal state [ 23 , 53 ].…”

Section: Discussionsupporting

confidence: 68%

Nrf2 Downregulation Contributes to Epithelial-to-Mesenchymal Transition in Helicobacter pylori-Infected Cells

Bacon

Seeneevassen

Fratacci

et al. 2022

Cancers

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Background: Gastric cancer, the fifth most common cancer worldwide, is mainly linked to Helicobacter pylori infection. H. pylori induces chronic inflammation of the gastric mucosa associated with high oxidative stress. Our study aimed at assessing the implication of Nrf2, a major regulator of cellular redox homeostasis, in H. pylori-induced gastric carcinogenesis. Methods: Using three different gastric epithelial cell lines, a non-cancerous (HFE-145) and two different subtypes of gastric cancer (AGS and MKN74), we analyzed the modulation of Nrf2 expression over time. After invalidation of Nrf2 by CRISPR-cas9, we assessed its role in H. pylori-induced epithelial-to-mesenchymal transition (EMT). Finally, we evaluated the expression of Nrf2 and ZEB1, a central EMT transcription factor, in human gastric tissues. Results: We first demonstrated that the Nrf2 signaling pathway is differentially regulated depending on the infection stage. Rapidly and transiently activated, Nrf2 was downregulated 24 h post-infection in a VacA-dependent manner. We then demonstrated that Nrf2 invalidation leads to increased EMT, which is even exacerbated after H. pylori infection. Finally, Nrf2 expression tended to decrease in human patients’ gastric mucosa infected with H. pylori. Conclusions: Our work supports the hypothesis that Nrf2 downregulation upon H. pylori infection participates in EMT, one of the most important events in gastric carcinogenesis.

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Section: Discussionsupporting

confidence: 68%

Nrf2 Downregulation Contributes to Epithelial-to-Mesenchymal Transition in Helicobacter pylori-Infected Cells

Bacon

Seeneevassen

Fratacci

et al. 2022

Cancers

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“…Weitzenböck et al found that Nrf2 suppression leads to the expression of CD44 and the development of epithelial-mesenchymal transition phenotype. Of note, treatment of Nrf2 depleted cells with BRAF or MYC inhibitor results in a higher survival rate of melanoma cells [ 50 ]. This shows that antioxidant intervention could be a game-changing strategy for improving melanoma patient survival.…”

Section: Resultsmentioning

confidence: 99%

“… Nrf2 silencing increases melanoma cell viability, invasiveness, and the risk of metastasis. [ 50 ] Wang et al, 2022 The A375, and A2058 cell lines Following treatment with erastin and RSL3, the level of CAMKK2 mRNA was significantly elevated. Phosphorylation of CAMKK2 reduces during ferroptosis.…”

Section: Methodsmentioning

confidence: 99%

The dual role of Nrf2 in melanoma: a systematic review

Malakoutikhah

Mohajeri

Dana

et al. 2023

BMC Mol and Cell Biol

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Melanoma is the most lethal type of skin cancer that originates from the malignant transformation of melanocytes. Although novel treatments have improved patient survival in melanoma, the overall prognosis remains poor. To improve current therapies and patients outcome, it is necessary to identify the influential elements in the development and progression of melanoma.Due to UV exposure and melanin synthesis, the melanocytic lineage seems to have a higher rate of ROS (reactive oxygen species) formation. Melanoma has been linked to an increased oxidative state, and all facets of melanoma pathophysiology rely on redox biology. Several redox-modulating pathways have arisen to resist oxidative stress. One of which, the Nrf2 (nuclear factor erythroid 2-related factor 2), has been recognized as a master regulator of cellular response to oxidative or electrophilic challenges. The activation of Nrf2 signaling causes a wide range of antioxidant and detoxification enzyme genes to be expressed. As a result, this transcription factor has lately received a lot of interest as a possible cancer treatment target.On the other hand, Nrf2 has been found to have a variety of activities in addition to its antioxidant abilities, constant Nrf2 activation in malignant cells may accelerate metastasis and chemoresistance. Hence, based on the cell type and context, Nrf2 has different roles in either preventing or promoting cancer. In this study, we aimed to systematically review all the studies discussing the function of Nrf2 in melanoma and the factors determining its alteration.

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“…In preclinical experiments, vemurafenib increases cell death [30], [31], decreases proliferation [32], [33] and also affects cell migration [34]- [36]. Furthermore, exposure to vemurafenib can also modify the released EVs' content [37], [38].…”

Section: Introductionmentioning

confidence: 99%

Extracellular vesicles promote migration despite vemurafenib treatment in malignant melanoma cells

Németh,

Bányai,

Dobos

et al. 2023

Preprint

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Extracellular vesicles (EVs) were found to be one group of the determining factors in intercellular communication and have been shown to have a crucial role in metastasis formation and drug resistance. Malignant melanoma (MM) is one of the deadliest forms of skin cancers, because of its high metastatic potential and often acquired resistance to oncotherapies. BRAF mutation is the most prevalent genetic aberration in MM, which implicates BRAF (e.g. vemurafenib) or combined BRAF/MEK inhibitor therapy. Herein, we analyzed the role of EVs in MM progression and investigated if EVs can maintain their role in metastasis promotion during vemurafenib treatment. Five pairs of syngeneic melanoma cell lines were treated with EVs isolated from their or their pair’s supernatant. EVs’ impact on melanoma cells’ proliferation was investigated using cell viability and spheroid growth assays. Furthermore, to investigate changes in cell migration, mean squared dis-placement (MSD) and total travelled distance (TTD) were calculated based on video microscopy measurements and single cell tracking. In most of the cases, EV treatments did not affect cell proliferation and spheroid growth, however, their migration-promoting role was more prominent. Additionally, EVs originating from more resistant cells could counteract the inhibitory effect of vemurafenib. In conclusion, our findings provide further details to understand the complex role of EVs in tumor promotion, progression and single-agent vemurafenib resistance in MM.

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Proteome analysis of NRF2 inhibition in melanoma reveals CD44 up‐regulation and increased apoptosis resistance upon vemurafenib treatment

Cited by 10 publications

References 37 publications

Nrf2 Downregulation Contributes to Epithelial-to-Mesenchymal Transition in Helicobacter pylori-Infected Cells

Nrf2 Downregulation Contributes to Epithelial-to-Mesenchymal Transition in Helicobacter pylori-Infected Cells

The dual role of Nrf2 in melanoma: a systematic review

Extracellular vesicles promote migration despite vemurafenib treatment in malignant melanoma cells

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