Aberrant human ClpP activation disturbs mitochondrial proteome homeostasis to suppress pancreatic ductal adenocarcinoma

Wang, Pengyu; Zhang, Tao; Wang, Xinjing; Xiao, Hongying; Li, Huiti; Zhou, Lingsha; Yang, Teng; Wei, Bingyan; Zhu, Zeyun; Zhou, Lu; Yang, Song; Lü, Xiang; Zhang, Yonghui; Huang, Yue; Gan, Jianhua; Yang, Cai‐Guang

doi:10.1016/j.chembiol.2022.07.002

Cited by 34 publications

(31 citation statements)

References 55 publications

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“…1b and 1c ). ICG-001 was initially characterized as a Wnt signaling pathway inhibitor, while it was recently screened as an activator for Hs ClpP 39 , 40 . Considering distinct scaffold of ICG-001 and the practicable synthesis of derivatives, we chose ICG-001 as a starting point for follow-up synthetic optimization 41 .…”

Section: Resultsmentioning

confidence: 99%

“…The pPSUMO- CLPP ΔN56 plasmid was transformed to E. coli Rosetta (DE3) cells for Hs ClpP expression 40 . The cells were cultured at 37 °C until OD 600 reached 0.6-0.8 and the expression of Hs ClpP was induced by 0.5 mM IPTG at 37 °C for 4 h. Cells were lysed in binding buffer (20 mM Tris-HCl, pH 7.5, 500 mM NaCl, 10 mM imidazole, and 10% glycerol).…”

Section: Methodsmentioning

confidence: 99%

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Anti-infective therapy using species-specific activators of Staphylococcus aureus ClpP

et al. 2022

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The emergence of methicillin-resistant Staphylococcus aureus isolates highlights the urgent need to develop more antibiotics. ClpP is a highly conserved protease regulated by ATPases in bacteria and in mitochondria. Aberrant activation of bacterial ClpP is an alternative method of discovering antibiotics, while it remains difficult to develop selective Staphylococcus aureus ClpP activators that can avoid disturbing Homo sapiens ClpP functions. Here, we use a structure-based design to identify (R)- and (S)-ZG197 as highly selective Staphylococcus aureus ClpP activators. The key structural elements in Homo sapiens ClpP, particularly W146 and its joint action with the C-terminal motif, significantly contribute to the discrimination of the activators. Our selective activators display wide antibiotic properties towards an array of multidrug-resistant staphylococcal strains in vitro, and demonstrate promising antibiotic efficacy in zebrafish and murine skin infection models. Our findings indicate that the species-specific activators of Staphylococcus aureus ClpP are exciting therapeutic agents to treat staphylococcal infections.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Anti-infective therapy using species-specific activators of Staphylococcus aureus ClpP

et al. 2022

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“…Therefore, targeting mitochondrial oxidative stress, including the mitochondria-located proteins, seems a promising treatment method. Wang’s team development a small molecule agonist ZG111 of the mitochondrial caseinolytic protease P (ClpP) that produces tumor inhibitory effects in pancreatic cancer cell lines and mouse models [ 49 ]. This study further proved that differentially expressed mitochondria-related genes are active in the oxidative stress pathway.…”

Section: Discussionmentioning

confidence: 99%

Mitochondria-Related Transcriptome Characterization Associated with the Immune Microenvironment, Therapeutic Response and Survival Prediction in Pancreatic Cancer

Dong

Liu

Zhang

et al. 2023

IJMS

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(1) Background: Pancreatic cancer (PC) is one of the most lethal tumors. Mitochondrial dysfunction has been reported to be involved in cancer development; however, its role in PC has remained unclear. (2) Methods: The differentially expressed NMGs were selected between PC and normal pancreatic tissue. The NMG-related prognostic signature was established by LASSO regression. A nomogram was developed based on the 12-gene signature combined with other significant pathological features. An extensive analysis of the 12 critical NMGs was performed in multiple dimensions. The expression of some key genes was verified in our external cohort. (3) Results: Mitochondria-related transcriptome features was obviously altered in PC compared with normal pancreas tissue. The 12-NMG signature showed good performance in predicting prognosis in various cohorts. The high- and low-risk groups exhibited notable diversity in gene mutation characteristics, biological characteristics, chemotherapy response, and the tumor immune microenvironment. Critical gene expression was demonstrated in our cohort at the mRNA and protein levels and in organelle localization. (4) Conclusions: Our study analyzed the mitochondrial molecular characterization of PC, proving the crucial role of NMGs in PC development. The established NMG signature helps classify patient subtypes in terms of prognosis prediction, treatment response, immunological features, and biological function, providing a potential therapeutic strategy targeting mitochondrial transcriptome characterization.

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“…In the past few years, multiple potent small-molecule HsClpP modulators have been reported and are classified as inhibitors and activators based on the binding sites 22,23 (Figure 1). ONC201 was originally discovered as a TRAIL receptor inducer and was subsequently identified as an HsClpP agonist.…”

Section: ■ Introductionmentioning

confidence: 99%

Discovery of a Novel Series of Homo sapiens Caseinolytic Protease P Agonists for Colorectal Adenocarcinoma Treatment via ATF3-Dependent Integrated Stress Response

Zhang,

Qiu,

Liu

et al. 2024

J. Med. Chem.

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Homo sapiens caseinolytic protease P (HsClpP) activation is a promising strategy for colon cancer treatment. In this study, CCG1423 was identified as a selective activator of HsClpP. After optimization, NCA029 emerged as the most potent compound, with an EC 50 of 0.2 μM against HsClpP. Molecular dynamics revealed that the affinity of NCA029 for the YYW aromatic network is crucial for its selectivity toward HsClpP. Furthermore, NCA029 displayed favorable pharmacokinetics and safety profiles and significantly inhibited tumor growth in HCT116 xenografts, resulting in 83.6% tumor inhibition. Mechanistically, NCA029 targeted HsClpP, inducing mitochondrial dysfunction and activating the ATF3-dependent integrated stress response, ultimately causing cell death in colorectal adenocarcinoma. These findings highlight NCA029 as an effective HsClpP activator with potential for colon cancer therapy.

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Aberrant human ClpP activation disturbs mitochondrial proteome homeostasis to suppress pancreatic ductal adenocarcinoma

Cited by 34 publications

References 55 publications

Anti-infective therapy using species-specific activators of Staphylococcus aureus ClpP

Anti-infective therapy using species-specific activators of Staphylococcus aureus ClpP

Mitochondria-Related Transcriptome Characterization Associated with the Immune Microenvironment, Therapeutic Response and Survival Prediction in Pancreatic Cancer

Discovery of a Novel Series of Homo sapiens Caseinolytic Protease P Agonists for Colorectal Adenocarcinoma Treatment via ATF3-Dependent Integrated Stress Response

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