bims-nurfca 2023-08-06 papers

Issue of 2023–08–06
seven papers selected by
Caner Geyik, Istinye University

Front Biosci (Landmark Ed). 2023 07 21. 28(7): 143

Cellular Modulators of the NRF2/KEAP1 Signaling Pathway in Prostate Cancer.

Giovanni Tossetta, Sonia Fantone, Daniela Marzioni, Roberta Mazzucchelli.

Prostate cancer is the second most common malignancy in men worldwide. Prostate cancer can be treated by surgery, radiotherapy and hormone therapy. The latter, in the form of androgen-deprivation therapy is needed to reduce prostate cancer progression at an advanced stage. Several studies demonstrated that oxidative stress is involved in cancer occurrence, development and progression and the Nuclear factor erythroid 2-related factor 2 (NRF2)/Kelch Like ECH Associated Protein 1 (KEAP1) pathway is affected by reactive oxygen species (ROS). Furthermore, the NRF2/KEAP1 signaling pathway has been investigated by several studies related to anti-androgen therapy, biochemical recurrence and radiotherapy. In this review we analysed the current literature regarding the indirect modulators involved in NRF2/KEAP1 pathway regulation and their role as possible therapeutic targets in prostate cancer cells.

Keywords: KEAP; NRF2; antioxidants; chemotherapy; modulator; prostate cancer; signaling

DOI: https://doi.org/10.31083/j.fbl2807143

J Exp Clin Cancer Res. 2023 Aug 01. 42(1): 190

TNFAIP2 confers cisplatin resistance in head and neck squamous cell carcinoma via KEAP1/NRF2 signaling.

Teng Xu, Yuemei Yang, Zhihong Chen, Jinsong Wang, Xiaolei Wang, Yang Zheng, Chao Wang, Yachen Wang, Zaiou Zhu, Xu Ding, Junbo Zhou, Gang Li, Hongchuang Zhang, Wei Zhang, Yunong Wu, Xiaomeng Song.

BACKGROUND: Drug resistance limits the treatment effect of cisplatin-based chemotherapy in head and neck squamous cell carcinoma (HNSCC), and the underlying mechanism is not fully understood. The aim of this study was to explore the cause of cisplatin resistance in HNSCC.
METHODS: We performed survival and gene set variation analyses based on HNSCC cohorts and identified the critical role of tumor necrosis factor alpha-induced protein 2 (TNFAIP2) in cisplatin-based chemotherapy resistance. Half-maximal inhibitory concentration (IC50) examination, colony formation assays and flow cytometry assays were conducted to examine the role of TNFAIP2 in vitro, while xenograft models in nude mice and 4-nitroquinoline N-oxide (4NQO)-induced HNSCC models in C57BL/6 mice were adopted to verify the effect of TNFAIP2 in vivo. Gene set enrichment analysis (GSEA) and coimmunoprecipitation coupled with mass spectrometry (Co-IP/MS) were performed to determine the mechanism by which TNFAIP2 promotes cisplatin resistance.
RESULTS: High expression of TNFAIP2 is associated with a poor prognosis, cisplatin resistance, and low reactive oxygen species (ROS) levels in HNSCC. Specifically, it protects cancer cells from cisplatin-induced apoptosis by inhibiting ROS-mediated c-JUN N-terminal kinase (JNK) phosphorylation. Mechanistically, the DLG motif contained in TNFAIP2 competes with nuclear factor-erythroid 2-related factor 2 (NRF2) by directly binding to the Kelch domain of Kelch-like ECH-associated protein 1 (KEAP1), which prevents NRF2 from undergoing ubiquitin proteasome-mediated degradation. This results in the accumulation of NRF2 and confers cisplatin resistance. Positive correlations between TNFAIP2 protein levels and NRF2 as well as its downstream target genes were validated in HNSCC specimens. Moreover, the small interfering RNA (siRNA) targeting TNFAIP2 significantly enhanced the cisplatin treatment effect in a 4NQO-induced HNSCC mouse model.
CONCLUSIONS: Our results reveal the antioxidant and cisplatin resistance-regulating roles of the TNFAIP2/KEAP1/NRF2/JNK axis in HNSCC, suggesting that TNFAIP2 might be a potential target in improving the cisplatin treatment effect, particularly for patients with cisplatin resistance.

Keywords: Cisplatin resistant; Head and neck squamous cell carcinoma; KEAP1/NRF2; Oxidative stress; TNFAIP2

DOI: https://doi.org/10.1186/s13046-023-02775-1

Biosci Rep. 2023 Aug 02. pii: BSR20222472. [Epub ahead of print]

Involvement of DPP3 in modulating oncological features and oxidative stress response in esophageal squamous cell carcinoma.

Mohit Arora, Sarita Kumari, Lokesh Kadian, Anupa G, Jay Singh, Anurag Kumar, Deepika Verma, Raja Pramanik, Sunil Kumar, Rajni Yadav, Anita Chopra, Shyam S Chauhan.

Resistance to therapy in (ESCC) is a critical clinical problem and the identification of novel therapeutic targets is highly warranted. Dipeptidyl peptidase III (DPP3) is a zinc-dependent aminopeptidase and functions in the terminal stages of protein turnover. Several studies have reported overexpression and oncogenic functions of DPP3 in numerous malignancies. This study aimed to determine the expression pattern and functional role of DPP3 in ESCC. DPP3 expression was assessed in normal and tumor tissues using qRT-PCR and corroborated with ESCC gene expression datasets from GEO and TCGA. DPP3 stable knockdown was performed in ESCC cells by shRNA and its effect on cell proliferation, migration, cell cycle, apoptosis, and activation of nuclear factor erythroid 2- related factor 2 (NRF2) pathway was assessed. The results suggested that DPP3 knockdown lead to reduced proliferation, increased apoptosis, and inhibited migration of ESCC cells. Additionally, DPP3 knockdown led to downregulation of the NRF2 pathway proteins, such as NRF2, G6PD, and NQO1 along with increased sensitivity towards oxidative stress-induced cell death and chemotherapy. Conclusively, these results demonstrate critical role of DPP3 in ESCC and DPP3/NRF2 axis may serve as an attractive therapeutic target against chemoresistance in this malignancy.

Keywords: Dipeptidyl peptidase; Nrf2; esophageal cancer; esophageal squamous cell carcinoma; oxidative stress

DOI: https://doi.org/10.1042/BSR20222472

Biomed Pharmacother. 2023 Jul 29. pii: S0753-3322(23)01039-9. [Epub ahead of print]165 115248

Activation of Nrf2 inhibits ferroptosis and protects against oxaliplatin-induced ototoxicity.

Kai Xu, Xu Chang, Xue Bai, Hong-Bing Liu, Xu-Bo Chen, Hong-Ping Chen, Yue-Hui Liu.

Oxaliplatin, as a third-generation platinum-based anticancer drug, is widely used in tumor therapy of many systems. Clinically, oxaliplatin has a number of serious side effects, most notably neuropathy and ototoxicity. The degeneration of cochlear hair cells is the main reason for the hearing loss caused by platinum-based drugs. However, the mechanism of oxaliplatin-induced cochlear hair cell death remains unclear. Ferroptosis is a novel cell injury pattern triggered by the accumulation of iron hydroperoxides in lipids and dependent on the participation of iron ions, which plays an important role in a variety of diseases. Whether ferroptosis is involved in oxaliplatin-induced ototoxicity has not been reported. In this study, we observed that oxaliplatin treatment resulted in lipid peroxidation and reactive oxygen species (ROS) accumulation in OC1 cells, which may be an early alteration in the occurrence of ferroptosis. Additional treatment with ferroptosis inducer or inhibitor significantly aggravated or ameliorated oxaliplatin-induced cytotoxicity. Similarly, inhibition of ferroptosis also protected cochlear hair cells against oxaliplatin-induced injury. In addition, the expression of nuclear factor erythroid 2-related factor2 (Nrf2) and heme oxygenase-1 (HO-1) was significantly increased after oxaliplatin treatment, and treatment with the Nrf2 agonist, resveratrol, dramatically attenuated cochlear hair cell damage induced by oxaliplatin. Activation of Nrf2 significantly decreased the expression of iron regulatory protein 2 (IRP-2) and reversed the expression of glutathione peroxidase 4 (GPX4). Collectively, our results demonstrated that activation of Nrf2 alleviates oxaliplatin-induced cochlear hair cell damage by inhibiting ferroptosis, which may be a new mechanism of oxaliplatin-induced ototoxicity.

Keywords: Ferroptosis; Hair cell; Nrf2; Ototoxicity; Oxaliplatin

DOI: https://doi.org/10.1016/j.biopha.2023.115248

Cell Commun Signal. 2023 08 01. 21(1): 188

Targeted Silencing of NRF2 by rituximab-conjugated nanoparticles increases the sensitivity of chronic lymphoblastic leukemia cells to Cyclophosphamide.

Atefeh Khodakarami, Mahsa Afsari Kashani, Atefeh Nazer, Armin Mahmoudsalehi Kheshti, Bentolhoda Rashidi, Vahid Karpisheh, Ali Masjedi, Shiva Abolhasani, Sepideh Izadi, Rafieh Bagherifar, Seyyed Sina Hejazian, Hamed Mohammadi, AliAkbar Movassaghpour, Abbas Ali Hosseinpour Feizi, Mohammad Hojjat-Farsangi, Farhad Jadidi-Niaragh.

BACKGROUND: Targeting influential factors in resistance to chemotherapy is one way to increase the effectiveness of chemotherapeutics. The nuclear factor erythroid 2-related factor 2 (Nrf2) pathway overexpresses in chronic lymphocytic leukemia (CLL) cells and appears to have a significant part in their survival and chemotherapy resistance. Here we produced novel nanoparticles (NPs) specific for CD20-expressing CLL cells with simultaneous anti-Nrf2 and cytotoxic properties.
METHODS: Chitosan lactate (CL) was used to produce the primary NPs which were then respectively loaded with rituximab (RTX), anti-Nrf2 Small interfering RNA (siRNAs) and Cyclophosphamide (CP) to prepare the final version of the NPs (NP-Nrf2_siRNA-CP). All interventions were done on both peripheral blood mononuclear cells (PBMCs) and bone marrow mononuclear cells (BMNCs).
RESULTS: NP-Nrf2_siRNA-CP had satisfying physicochemical properties, showed controlled anti-Nrf2 siRNA/CP release, and were efficiently transfected into CLL primary cells (both PBMCs and BMNCs). NP-Nrf2_siRNA-CP were significantly capable of cell apoptosis induction and proliferation prevention marked by respectively decreased and increased anti-apoptotic and pro-apoptotic factors. Furthermore, use of anti-Nrf2 siRNA was corresponding to elevated sensitivity of CLL cells to CP.
CONCLUSION: Our findings imply that the combination therapy of malignant CLL cells with RTX, CP and anti-Nrf2 siRNA is a novel and efficient therapeutic strategy that was capable of destroying malignant cells. Furthermore, the use of NPs as a multiple drug delivery method showed fulfilling properties; however, the need for further future studies is undeniable. Video Abstract.

Keywords: Chemo-resistance; Chronic lymphocytic leukemia (CLL); Cyclophosphamide; NRF2; Rituximab

DOI: https://doi.org/10.1186/s12964-023-01213-1