作者: Li, Chunwei ; Wang, Longhao ; Wei, Yujie ; Song, Yiqiong ; Zheng, Yuanyuan ; Yang, Yaqi ; Zhu, Lili ; Zhang, Yixing ; Chao, Ke ; Ge, Yahao ; Li, Lifeng ; Jia, Lanqi ; Zhao, Jie ; Sun, Shilong

Lung cancer is one of the most common malignant tumors. Despite decades of research, the treatment of lung cancer remains challenging. Non-small cell lung cancer (NSCLC) is the primary type of lung cancer and is a significant focus of research in lung cancer treatment. The deubiquitinase ubiquitin-specific protease 28 (USP28) plays a role in the progression of various tumors and serves as a potential therapeutic target. This study aims to determine the role of USP28 in the progression of NSCLC. We examined the impact of the USP28 inhibitor AZ1 on the cell cycle, apoptosis, DNA damage response, and cellular immunogenicity in non-small cell lung cancer. We observed that AZ1 and siUSP28 induce DNA damage, leading to the activation of Noxa-mediated mitochondrial apoptosis. The dsDNA and mtDNA released from DNA damage and mitochondrial apoptosis activate tumor cell immunogenicity through the cGAS-STING signaling pathway. Simultaneously, targeting USP28 promotes the degradation of c-MYC, resulting in cell cycle arrest and inhibition of DNA repair. This further promotes DNA damage-induced cell apoptosis mediated by the Noxa protein, thereby enhancing tumor cell immunogenicity mediated by dsDNA and mtDNA. Moreover, we found that the combination of AZ1 and cisplatin (DDP) can enhance therapeutic efficacy, thereby providing a new strategy to overcome cisplatin resistance in NSCLC. These findings suggest that targeting USP28 and combining it with cisplatin are feasible strategies for treating NSCLC.

2023-11-01·Anticancer Research

NAD(P)H:quinone Oxidoreductase 1 Is Involved in AZ-1-induced Apoptotic Effects in Nasopharyngeal Carcinoma TW01 Cells

Article

作者: Lin, Sheng-Chieh ; Lo, Shu-Chin ; Yu, Si-Jie ; Wu, Yen-Ting ; Lin, Yuh-Ling ; Lan, Yu-Yan ; Hsu, Chung-Chi ; Chen, Pei-Jung ; Liu, Fang-Qi

BACKGROUND/AIMCurrent NPC treatment methods have improved the 5-year survival rates of patients; however, some patients do not benefit from the treatments. Therefore, the existing treatment methods or new drugs must be developed to improve the patient's prognosis. NAD (P)H:quinone oxidoreductase 1 (NQO1), an electron reductase highly expressed in various cancers, can convert aziridinyl-substituted quinone-derived compound into an alkylating agent, resulting in cell apoptosis. Therefore, a di-aziridinyl-substituted quinone-derived compound, AZ-1, was designed previously. The present study investigated whether AZ-1 has anticancer activities in NPC cells and explored the underlying mechanism.MATERIALS AND METHODSNPC-TW01 cells were used in the study, and 3-(4,5-dimethylthiazol- 2-yl)-2,5-diphenyltetrazolium bromide, colony formation, terminal deoxynucleotidyl transferase dUTP nick end labeling, and immunoblotting assays were performed to assess the cell viability, cell survival, DNA fragmentation, and protein expression, respectively.RESULTSThe results show that AZ-1 significantly inhibited the viability and survival of NPC-TW01 cells. AZ-1 also induced the expression of cleaved PARP, cleaved caspase-8, cleaved caspase-9, and cleaved caspase-3, and triggered DNA fragmentation in NPC-TW01 cells. In addition, AZ-1 induced γH2AX expression, a DNA damage marker, in NPC-TW01 cells. Treatment with dicoumarol, an NQO1 activity inhibitor, not only reversed AZ-1-induced cell viability inhibition but also decreased AZ-1-induced expression of γH2AX, cleaved caspase-8, cleaved caspase-9, and cleaved caspase-3.CONCLUSIONNQO1 reverses AZ-1-triggered cell viability inhibition, DNA damage, and apoptosis. The findings of this study may provide a basis for the possible clinical application of AZ-1 in the treatment of NPC to improve the prognosis of patients with NPC.

2023-01-01·Nature Biotechnology

A proteome-scale map of the SARS-CoV-2-human contactome.

Article

作者: Dugied, Guillaume ; Li, Roujia ; Willems, Luc ; Young, Veronika ; Heinig, Matthias ; Krappmann, Daniel ; Sauer, Mayra ; Taipale, Mikko ; Spirohn, Kerstin ; Hill, David E ; Pogoutse, Oxana ; Strobel, Alexandra ; Brun, Christine ; Dohai, Bushra ; Rothballer, Simin T ; Knapp, Jennifer J ; Coté, Atina G ; Calderwood, Michael A ; Lin, Chung-Wen ; Maseko, Sibusiso B ; Jacob, Yves ; Vidal, Marc ; Hazelwood, Isaiah ; la Rosa, Nora Marín-de ; Liu, Betty B ; Twizere, Jean-Claude ; Kishore, Nishka ; Pons, Carles ; Coloma, Patricia A Rodriguez ; Hao, Tong ; Pandiarajan, Ramakrishnan ; Demeret, Caroline ; Tofaute, Marie J ; Aloy, Patrick ; Altmann, Melina ; Rayhan, Ashyad ; Zanzoni, Andreas ; Giuliana, Paolo ; Sheykhkarimli, Dayag ; Cassonnet, Patricia ; Roth, Frederick P ; Halder, Hridi ; Lambourne, Luke ; Falter, Claudia ; Poirson, Juline ; Kim, Dae-Kyum ; Nguyen, Maria ; Schwehn, Patrick ; Laval, Florent ; Falter-Braun, Pascal ; Vergara, Lena Elorduy ; Weller, Benjamin

Understanding the mechanisms of coronavirus disease 2019 (COVID-19) disease severity to efficiently design therapies for emerging virus variants remains an urgent challenge of the ongoing pandemic. Infection and immune reactions are mediated by direct contacts between viral molecules and the host proteome, and the vast majority of these virus-host contacts (the 'contactome') have not been identified. Here, we present a systematic contactome map of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) with the human host encompassing more than 200 binary virus-host and intraviral protein-protein interactions. We find that host proteins genetically associated with comorbidities of severe illness and long COVID are enriched in SARS-CoV-2 targeted network communities. Evaluating contactome-derived hypotheses, we demonstrate that viral NSP14 activates nuclear factor κB (NF-κB)-dependent transcription, even in the presence of cytokine signaling. Moreover, for several tested host proteins, genetic knock-down substantially reduces viral replication. Additionally, we show for USP25 that this effect is phenocopied by the small-molecule inhibitor AZ1. Our results connect viral proteins to human genetic architecture for COVID-19 severity and offer potential therapeutic targets.

100 项与 AZ1 相关的药物交易

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