作者: Rubbi, Carlos ; Clifford, Rachael E ; Govindarajah, Naren ; Vimalachandran, Dale ; Francies, Hayley ; Sutton, Paul A ; Glenn, Mark ; Bowden, David ; Fowler, Hayley ; Buczacki, Simon J A ; Wall, Michael ; Mandal, Amit ; Fok, Matthew ; Hughes, Jonathan ; Parsons, Jason L

PURPOSE:

Patients with locally advanced rectal cancer often require neoadjuvant chemoradiation therapy to downstage the disease, but the response is variable with no predictive biomarkers. We have previously revealed through proteomic profiling that myoferlin is associated with response to radiation therapy. The aims of this study were to further validate this finding and explore the potential for myoferlin to act as a prognostic and/or therapeutic target.

METHODS AND MATERIALS:

Immunohistochemical analysis of a tissue microarray (TMA) for 111 patients was used to validate the initial proteomic findings. Manipulation of myoferlin was achieved using small interfering RNA, a small molecular inhibitor (wj460), and a CRISPR-Cas9 knockout cell line. Radiosensitization after treatment was assessed using 2-dimensional clonogenic assays, 3-dimensional spheroid models, and patient-derived organoids. Underlying mechanisms were investigated using electrophoresis, immunofluorescence, and immunoblotting.

RESULTS:

Analysis of both the diagnostic biopsy and tumor resection samples confirmed that low myoferlin expression correlated with a good response to neoadjuvant long-course chemoradiation therapy. High myoferlin expression was associated with spread to local lymph nodes and worse 5-year survival (P = .01; hazard ratio, 3.5; 95% CI, 1.27-10.04). This was externally validated using the Stratification in Colorectal Cancer database. Quantification of myoferlin using immunoblotting in immortalized colorectal cancer cell lines and organoids demonstrated that high myoferlin expression was associated with increased radioresistance. Biological and pharmacologic manipulation of myoferlin resulted in significantly increased radiosensitivity across all cell lines in 2-dimensional and 3-dimensional models. After irradiation, myoferlin knockdown cells had a significantly impaired ability to repair DNA double-strand breaks. This appeared to be mediated via nonhomologous end-joining.

CONCLUSIONS:

We have confirmed that high expression of myoferlin in rectal cancer is associated with poor response to neoadjuvant therapy and worse long-term survival. Furthermore, the manipulation of myoferlin led to increased radiosensitivity in vitro. This suggests that myoferlin could be targeted to enhance the sensitivity of patients with rectal cancer to radiation therapy, and further work is required.

2022-10-01·Future medicinal chemistry

Discovery of 1,5-diaryl-1,2,4-triazole Derivatives as Myoferlin Inhibitors and Their Antitumor Effects in Pancreatic Cancer

Article

作者: Yi, Zhengfang ; Kan, Weiqiong ; He, Peng ; Li, Yunqi ; He, Yuan ; Zhang, Ting ; Gu, Haijun ; Chen, Yihua ; Guan, Tian

Aim: The first inhibitor targeting myoferlin (MYOF), WJ460, bears poor metabolic stability and water solubility. Therefore, this study aimed to improve the drug-like properties of WJ460. Materials & methods: The authors synthesized an array of 1,5-diaryl-1,2,4-triazole analogs and appraised the binding activities with MYOF and their antiproliferative and antimigratory activities against pancreatic cancer cells. Results: Molecular docking and surface plasmon resonance results showed that E4 was directly bound to the MYOF-C2D domain. E4 effectively inhibited the proliferation and migration of pancreatic cancer cells in vitro. An in silico study suggested that the water solubility of E4 was improved by about 22-times than that of WJ460. Conclusion: The findings suggested that the druglike ability of E4 was significantly improved.

2022-07-01·Redox biology1区 · 生物学

Myoferlin targeting triggers mitophagy and primes ferroptosis in pancreatic cancer cells

1区 · 生物学

ArticleOA

作者: Rademaker, Gilles ; Anania, Sandy ; Maloujahmoum, Naïma ; Boumahd, Yasmine ; Luis, Géraldine ; Castronovo, Vincent ; De Tullio, Pascal ; Bellahcène, Akeila ; Sounni, Nor Eddine ; Agirman, Ferman ; Thiry, Marc ; Peulen, Olivier ; Liégeois, Maude ; Wissocq, Tom ; Peiffer, Raphaël

Myoferlin, an emerging oncoprotein, has been associated with a low survival in several cancer types including pancreas ductal adenocarcinoma where it controls mitochondria structure and respiratory functions. Owing to the high susceptibility of KRAS-mutated cancer cells to iron-dependent cell death, ferroptosis, and to the high iron content in mitochondria, we investigated the relation existing between mitochondrial integrity and iron-dependent cell death. We discovered that myoferlin targeting with WJ460 pharmacological compound triggered mitophagy and ROS accumulation culminating with lipid peroxidation and apoptosis-independent cell death. WJ460 caused a reduction of the abundance of ferroptosis core regulators x_c^- cystine/glutamate transporter and GPX-4. Mitophagy inhibitor Mdivi1 and iron chelators inhibited the myoferlin-related ROS production and restored cell growth. Additionally, we reported a synergic effect between ferroptosis inducers, erastin and RSL3, and WJ460.

100 项与 WJ-460 相关的药物交易

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