DRUG RESISTANCE UPDATES
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2025
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IF 21.7
Muhammad Zubair Saleem,Ruyi Huang,Yingying Huang,Xin Guo,Yang Liu,Miao Gao,Yinjuan Fan,Zhe-Sheng Chen,Zun-Fu Ke,Shengnan Ye,Jianhua Xu
Aims TRAP1 is involved in metabolic reprogramming and promotes drug resistance. We aimed to explore whether a novel HSP90 inhibitor, C210, overcomes doxorubicin (DOX) resistance of quiescent breast cancer cells by targeting TRAP1. Methods Breast cancer cells were induced to quiescence by hypoxia and low glucose. The relationship of cell metabolism with HSP90 and TRAP1 was investigated by Western blotting, ECAR, OCR, mitochondrial complex activity, and proteomic analysis. The targets of C210 and their functions were analyzed by SPR and immunoprecipitation. The antitumor effect in vivo was investigated with mouse tumor model. Results In hypoxia and glucose deprivation, breast cancer cells exhibited elevated TRAP1 and an OXPHOS-enhanced quiescent phenotype. These cells were highly resistant to DOX but more sensitive to C210. C210 disrupted TRAP1's interaction with OXPHOS-associated client proteins, prompting proteasome-dependent degradation of these proteins, thereby reducing OCR, mitochondrial ATP production and resulting in selective elimination of the quiescent cancer cells by inducing mitochondrial apoptosis which could be reversed by exogenous ATP. Moreover, C210 targeted glycolytic, amino acid, and β-oxidation-associated proteome. C210 demonstrated promising in vivo anticancer efficacy which was particularly related to OXPHOS inhibition. Conclusions C210 eliminates DOX-resistant quiescent breast cancer cells by targeting TRAP1-dependent bioenergetics.
研究领域:
肿瘤学
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分子生物学
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药物研发
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DOI
PubMed
高影响因子
MOLECULAR AND CELLULAR BIOCHEMISTRY
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2020
·Vol. 476
·期 2
·1075-1082
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IF 2.795
Zhang Xiaowei,Dong Yu,Gao Miao,Hao Minfeng,Ren Hui,Guo Ling,Guo Hua
The tumor necrosis factor receptor-associated protein 1 (TRAP1) is associated with the occurrence and development of various diseases, including inflammation and cancer. However, the role and mechanism of TRAP1 in the development of lung cancer need to be further explored. Therefore, the purpose of this study is to investigate the role of TRAP1 in the regulation of apoptosis by cisplatin and its special mechanism. The RT-qPCR and Western blot were used to detect the mRNA and protein expression of ANGPTL4 in A549 and H1299 cells, respectively. And the cell apoptosis and cell cycle were measured by flow cytometry (FCM). The expression of genes related to apoptosis and drug resistance as well as the cell cycle regulators, including MDM2, CyclinB1, and CDK1, were detected by Western blot. Finally, the reactive oxygen species (ROS) indicator DCFH-DA was performed to detect the generation of ROS, and the mitochondrial membrane potential (ΔΨm) was detected by JC-1 staining. The results showed that the expression of TRAP1 was significantly increased in A549/DDP and H1299/DDP than A549 and H1299 cells. Further research found that knockdown of TRAP1 induced apoptosis and caused G2/M cell cycle arrest in A549/DDP and H1299/DDP cells. What is more, siTRAP1 reduced the relative JC-1 polymer monomer fluorescence ratio and decreased the ΔΨm, up-regulated the expression of Cytochrome C. Importantly, siTRAP1 induces ROS-dependent mitochondrial dysfunction. It is suggested that that TRAP1 suppresses cisplatin-induced apoptosis by promoting ROS-dependent mitochondrial dysfunction.
研究领域:
肿瘤学
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细胞生物学
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药理学
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DOI
PubMed
高影响因子
Nature Nanotechnology
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2025
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IF 34.9
Zhao Kai,Yan Yu,Jin Xiao-Kang,Pan Ting,Zhang Shi-Man,Yang Chi-Hui,Rao Zhi-Yong,Zhang Xian-Zheng
Chemoresistance and immunosuppression are common obstacles to the efficacy of chemo-immunotherapy in colorectal cancer (CRC) and are regulated by mitochondrial chaperone proteins. Here we show that the disruption of the tumour necrosis factor receptor-associated protein 1 ( TRAP1 ) gene, which encodes a mitochondrial chaperone in tumour cells, causes the translocation of cyclophilin D in tumour cells. This process results in the continuous opening of the mitochondrial permeability transition pore, which enhances chemotherapy-induced cell necrosis and promotes immune responses. On the basis of this discovery we developed an oral CRISPR–Cas9 delivery system based on zwitterionic and polysaccharide polymer-coated nanocomplexes that disrupts the TRAP1 gene in CRC. This system penetrates the intestinal mucus layer and undergoes epithelial transcytosis, accumulating in CRC tissues. It enhances chemotherapeutic efficacy by overcoming chemoresistance and activating the tumour immune microenvironment in orthotopic, chemoresistant and spontaneous CRC models, with remarkable synergistic antitumour effects. This oral CRISPR–Cas9 delivery system represents a promising therapeutic strategy for the clinical management of CRC.
研究领域:
肿瘤学
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分子生物学
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基因编辑
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纳米医学
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高影响因子
CELL BIOLOGY AND TOXICOLOGY
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2026
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IF 5.7
Qu Yinmeng,Liu Renjie,Chen Xuan,Wu Peifan,Zhao Yuhao
Diabetic-associated cognitive dysfunction (DACD) is a severe complication of diabetes characterized by mitochondrial failure in hippocampal neurons, yet its precise molecular drivers remain poorly understood. Here, hydroxysteroid dehydrogenase-like 2 (HSDL2) was identified as a key mitochondrial-related protein significantly upregulated in DACD models. Knockdown of HSDL2 alleviated cognitive impairment, synaptic loss, and neuronal apoptosis in DACD mice. Mechanistic investigations revealed that HSDL2 promoted mitochondrial dysfunction and neuronal apoptosis by downregulating TNF receptor-associated protein 1 (TRAP1). Furthermore, HSDL2 was identified as a novel substrate of the desuccinylase sirtuin 5 (SIRT5). SIRT5 mediated HSDL2 desuccinylation at the K42 site to stabilize its protein, leading to its upregulation. Importantly, SIRT5 was upregulated in DACD, and its knockdown mitigated hippocampal damage and cognitive dysfunction. This study unveiled a novel SIRT5/HSDL2/TRAP1 axis in DACD pathogenesis, wherein SIRT5 upregulation drove HSDL2 desuccinylation and stabilization, ultimately promoting mitochondrial dysfunction and cognitive decline via downregulation of TRAP1.
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高影响因子
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