EUROPEAN JOURNAL OF PHARMACOLOGY
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2024
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IF 4.2
Xuening Chen,Changkun Chen,Chengmiao Luo,Jianyong Liu,Zhonghui Lin
The emergence of chemoresistance poses a significant challenge to the efficacy of DNA-damaging agents in cancer treatment, in part due to the inherent DNA repair capabilities of cancer cells. The Ku70/80 protein complex (Ku) plays a central role in double-strand breaks (DSBs) repair through the classical non-homologous end joining (c-NHEJ) pathway, and has proven to be one of the most promising drug target for cancer treatment when combined with radiotherapy or chemotherapy. In this study, we conducted a high-throughput screening of small-molecule inhibitors targeting the Ku complex by using a fluorescence polarization-based DNA binding assay. From a library of 11,745 small molecules, UMI-77 was identified as a potent Ku inhibitor, with an IC 50 value of 2.3 μM. Surface plasmon resonance and molecular docking analyses revealed that UMI-77 directly bound the inner side of Ku ring, thereby disrupting Ku binding with DNA. In addition, UMI-77 also displayed potent inhibition against MUS81-EME1, a key player in homologous recombination (HR), demonstrating its potential for blocking both NHEJ- and HR-mediated DSB repair pathways. Further cell-based studies showed that UMI-77 could impair bleomycin-induced DNA damage repair, and significantly sensitized multiple cancer cell lines to the DNA-damaging agents. Finally, in a mouse xenograft tumor model, UMI-77 significantly enhanced the chemotherapeutic efficacy of etoposide with little adverse physiological effects. Our work offers a new avenue to combat chemoresistance in cancer treatment, and suggests that UMI-77 could be further developed as a promising candidate in cancer treatment.
研究领域:
癌症生物学
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药理学
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分子生物学
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化疗
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Journal of Fungi
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2023
·Vol. 9
·期 1
·94
·
IF 4.7
Azizullah,Muhammad Noman,Yizhou Gao,Hui Wang,Xiaohui Xiong,Jiajing Wang,Dayong Li,Fengming Song
SUMOylation is an essential protein modification process that regulates numerous crucial cellular and biochemical processes in phytopathogenic fungi, and thus plays important roles in multiple biological functions. The present study characterizes the SUMOylation pathway components, including SMT3 (SUMO), AOS1 (an E1 enzyme), UBC9 (an E2 enzyme), and MMS21 (an E3 ligase), inFusarium oxysporumf. sp.niveum(Fon), the causative agent of watermelon Fusarium wilt, in terms of the phylogenetic relationship, gene/protein structures, and basic biological functions. The SUMOylation components FonSMT3, FonAOS1, FonUBC9, and FonMMS21 are predominantly located in the nucleus.FonSMT3,FonAOS1,FonUBC9, andFonMMS21are highly expressed in the germinating macroconidia, but their expression is downregulated gradually in infected watermelon roots with the disease progression. The disruption ofFonUBA2andFonSIZ1seems to be lethal inFon. The deletion mutant strains forFonSMT3,FonAOS1,FonUBC9, andFonMMS21are viable, but exhibit significant defects in vegetative growth, asexual reproduction, conidial morphology, spore germination, responses to metal ions and DNA-damaging agents, and apoptosis. The disruption ofFonSMT3,FonAOS1,FonUBC9, andFonMMS21enhances sensitivity to cell wall-perturbing agents, but confers tolerance to digestion by cell wall-degrading enzymes. Furthermore, the disruption ofFonSMT3,FonAOS1, andFonUBC9negatively regulates autophagy inFon. Overall, these results demonstrate that the SUMOylation pathway plays vital roles in regulating multiple basic biological processes inFon, and, thus, can serve as a potential target for developing a disease management approach to control Fusarium wilt in watermelon.Keywords:asexual reproduction;cell death;cell wall integrity;Fusarium oxysporumf. sp.niveum;mycelial growth;stress response;SUMOylation pathway;watermelon
研究领域:
植物病理学
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分子生物学
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真菌遗传学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）