The Role of NQO1 in Ovarian Cancer

Tossetta, Giovanni; Fantone, Sonia; Goteri, Gaia; Giannubilo, Stefano Raffaele; Ciavattini, Andrea; Marzioni, Daniela

doi:10.3390/ijms24097839

Cited by 41 publications

(24 citation statements)

References 114 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…CAP, a natural small molecule derived from chili peppers, has been identified and verified to modulate the KEAP1-NRF2-ARE pathway in our study. This signaling plays a key role in several cancerous and non-cancerous diseases [33][34][35][36][37] . Therefore, it is a promising therapeutic target for combatting free radical damage associated with numerous conditions, including Alzheimer's disease 38 , chronic kidney disease 39 , cardiovascular disease 40 , cancer and aging 41 .…”

Section: Discussionmentioning

confidence: 99%

Capsaicin acts as a novel NRF2 agonist to suppress ethanol induced gastric mucosa oxidative damage by directly disrupting the KEAP1-NRF2 interaction

Gao,

Guo,

Liu

et al. 2024

Preprint

View full text Add to dashboard Cite

Ethanol induced oxidative damage to the gastric mucosa is one of the causes of gastritis and gastric ulcers. The KEAP1/NRF2 system stands as the principal regulator of reactive oxygen stress (ROS). Capsaicin (CAP), a naturally small molecule from chili, is recognized for its antioxidant and anti-inflammatory attributes. Yet, the mechanistic action remains largely unknown. In the study, we established an in vitro oxidative stress model using ethanol-exposed human gastric mucosal epithelial (GES-1) cells. We found that CAP pretreatment effectively mitigated ROS levels and preserved mitochondrial integrity. Proteomic analysis indicated a significant enrichment of antioxidant-associated pathways. Intriguingly, CAP augmented NRF2 protein expression and facilitated its nuclear translocation, thereby amplifying the transcription and translation of downstream antioxidant response elements (ARE), such as HO-1, NQO1, Trx and GSS. These observations were congruent in hydrogen peroxide-exposed mesenchymal stem cells, which indicates the universality of its antioxidant ability. Furthermore, CAP was found to inhibit the KEAP1-NRF2 interaction, and it failed to trigger the activation of NRF2 after KEAP1 knockout in 293T. CAP specifically interacts with the Kelch domain of KEAP1 and binds to allosteric sites. To enhance drug safety, we also formulated and characterized IR-HSA@CAP nanoparticles. In vivo assessments corroborated that CAP markedly curtailed ROS and invigorated the NRF2/ARE pathway. Additionally, CAP modulated inflammatory markers, reducing IL-1β, TNF-α, IL-6, and CXCL1/KC(IL-8), while elevating IL-10 in gastric tissues. Given that the non-covalent binding modality of natural compounds to KEAP1 remains underreported, CAP may emerge as a pioneering direct inhibitor of the KEAP1-NRF2 interaction.

show abstract

Section: Discussionmentioning

confidence: 99%

Capsaicin acts as a novel NRF2 agonist to suppress ethanol induced gastric mucosa oxidative damage by directly disrupting the KEAP1-NRF2 interaction

Gao,

Guo,

Liu

et al. 2024

Preprint

View full text Add to dashboard Cite

show abstract

“…Moreover, with each successive chemotherapy treatment and increased dosage, the intervals between treatments shorten, leading to heightened chemoresistance and a deteriorating prognosis 5 . Research suggests that heightened antioxidant capacities within cancer cells and increased capabilities to expel drugs are primary contributors to chemoresistance 6–9 . Additionally, an enhanced ability to repair DNA damage and the inactivation of tumor cell apoptosis are other prevalent factors 10,11 .…”

Section: Introductionmentioning

confidence: 99%

BIRC5 facilitates cisplatin‐chemoresistance in a m⁶A‐dependent manner in ovarian cancer

Fan,

Pan,

Jia

et al. 2023

Cancer Medicine

View full text Add to dashboard Cite

Cisplatin‐based chemotherapy is the standard treatment for metastatic ovarian cancer (OC). However, chemoresistance continues to pose significant clinical challenges. Recent research has highlighted the baculoviral inhibitor of the apoptosis protein repeat‐containing 5 (BIRC5) as a member of the inhibitor of the apoptosis protein (IAP) family. Notably, BIRC5, which has robust anti‐apoptotic capabilities, is overexpressed in numerous cancers. Its dysfunction has been linked to challenges in cancer treatment. Yet, the role of BIRC5 in the chemoresistance of OC remains elusive. In our present study, we observed an upregulation of BIRC5 in cisplatin‐resistant cell lines. This upregulation was associated with enhanced chemoresistance, which was diminished when the expression of BIRC5 was silenced. Intriguingly, BIRC5 exhibited a high number of N6‐methyladenosine (m6A) binding sites. The modification of m6A was found to enhance the expression of BIRC5 by recognizing and binding to the 3′‐UTR of mRNA. Additionally, the insulin‐like growth factor 2 mRNA‐binding protein 1 (IGF2BP1) was shown to stabilize BIRC5 mRNA, synergizing with METTL3 and intensifying chemoresistance. Supporting these in vitro findings, our in vivo experiments revealed that tumors were significantly smaller in size and volume when BIRC5 was silenced. This reduction was notably counteracted by co‐silencing BIRC5 and overexpressing IGF2BP1. Our results underscored the pivotal role of BIRC5 in chemoresistance. The regulation of its expression and the stability of its mRNA were influenced by m6A modifications involving both METTL3 and IGF2BP1. These insights presented BIRC5 as a promising potential therapeutic target for addressing cisplatin resistance in OC.

show abstract

“…From a molecular standpoint, the increased antioxidant capacity of the cancer cells and the surrounding microenvironment was the primary cause of chemoresistance in ovarian cancer cells 9,10 . NQO1 is an antioxidant enzyme that takes part in ovarian cancer onset and progression 10 . Its modulator, Nrf2 mediates antioxidant pathway and serves as a resistance mechanism in proteasome inhibitor‐resistant cells 11 .…”

Section: Introductionmentioning

confidence: 99%

Tryptophan metabolism enzymes are potential targets in ovarian clear cell carcinoma

Zhang,

Gao,

Wang

et al. 2023

Cancer Medicine

View full text Add to dashboard Cite

AimAs the second most prevalent subtype of epithelial ovarian cancers, ovarian clear cell carcinoma (OCCC) is known for its chemoresistance to conventional platinum‐based therapy. In this work, we examined the tryptophan (Trp) metabolism enzymes' differential expression in patients with OCCC to assess the potential for personalised treatment.MethodsA total of 127 OCCC tissues were used to construct tissue microarrays, and immunohistochemistry (IHC) staining of the Trp enzymes IDO1, IDO2, TDO2 and IL4I1 was performed. The correlations between Trp enzyme expression and clinical characteristics were analysed.ResultsPositive IDO1, IDO2, TDO2 and IL4I1 staining was identified in 26.8%, 94.5%, 75.6% and 82.7% of OCCC respectively. IDO1‐positive samples were more common in the chemoresistant group than in the platinum‐sensitive group (46.7% vs. 19.8%). Moreover, positive expression of IDO1, TDO2 and IL4I1 was related to advanced stage, metastasis, bilateral tumours, endometriosis and tumour rupture (p < 0.05) respectively. Univariate analysis revealed a significant association between bilateral tumours, lymph node metastasis, advanced stage, distant metastasis and aberrant cytology with a poor prognosis for OCCC, while the absence of residual tumour was correlated with a favourable outcome (p < 0.05). However, only bilateral tumours and lymph node metastases were related to a poor prognosis after multivariate analysis.ConclusionThis is the first study to investigate the expression of the Trp enzymes IDO1, IDO2, TDO2 and IL4I1 in OCCC tissues. IDO2, TDO2 and IL4I1 were detected in the majority of OCCC. Clinical traits were correlated with IDO1, IDO2, TDO2 and IL4I1 expression. IDO1 may be used as a therapeutic target given the large percentage of chemoresistant cases with IDO1 expression. These results will aid the development of personalised therapies for OCCC.

show abstract

The Role of NQO1 in Ovarian Cancer

Cited by 41 publications

References 114 publications

Capsaicin acts as a novel NRF2 agonist to suppress ethanol induced gastric mucosa oxidative damage by directly disrupting the KEAP1-NRF2 interaction

Capsaicin acts as a novel NRF2 agonist to suppress ethanol induced gastric mucosa oxidative damage by directly disrupting the KEAP1-NRF2 interaction

BIRC5 facilitates cisplatin‐chemoresistance in a m⁶A‐dependent manner in ovarian cancer

Tryptophan metabolism enzymes are potential targets in ovarian clear cell carcinoma

Contact Info

Product

Resources

About

The Role of NQO1 in Ovarian Cancer

Cited by 41 publications

References 114 publications

Capsaicin acts as a novel NRF2 agonist to suppress ethanol induced gastric mucosa oxidative damage by directly disrupting the KEAP1-NRF2 interaction

Capsaicin acts as a novel NRF2 agonist to suppress ethanol induced gastric mucosa oxidative damage by directly disrupting the KEAP1-NRF2 interaction

BIRC5 facilitates cisplatin‐chemoresistance in a m6A‐dependent manner in ovarian cancer

Tryptophan metabolism enzymes are potential targets in ovarian clear cell carcinoma

Contact Info

Product

Resources

About

BIRC5 facilitates cisplatin‐chemoresistance in a m⁶A‐dependent manner in ovarian cancer