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Dual-Targeting of ATOX1 and ROCK1: A Potent Strategy to Potentiate the Inhibition of Lung Adenocarcinoma Proliferation.

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Titel: Dual-Targeting of ATOX1 and ROCK1: A Potent Strategy to Potentiate the Inhibition of Lung Adenocarcinoma Proliferation.
Autoren: Ma, Sailong1,2 (AUTHOR), Peng, Changqing1,2 (AUTHOR), Xiong, Qi1,2 (AUTHOR), Yang, Liying1,2 (AUTHOR), Yan, Pengcheng1,2 (AUTHOR), Huo, Zitian1,2 (AUTHOR) huozitian@126.com, Wang, Guoping1,2 (AUTHOR) wanggp@hust.edu.cn
Quelle: Cancers. Sep2025, Vol. 17 Issue 17, p2887. 15p.
Schlagwörter: *COPPER metabolism, *ADENOCARCINOMA, *IN vitro studies, *SMALL interfering RNA, *BIOLOGICAL models, *ION pumps, *CARRIER proteins, *COLORIMETRY, *DATA analysis, *RESEARCH funding, *CELL proliferation, *IMMUNOGLOBULINS, *ENZYME inhibitors, *FLUORESCENT antibody technique, *CELLULAR signal transduction, *IN vivo studies, *DESCRIPTIVE statistics, *IMMUNOHISTOCHEMISTRY, *CELL lines, *LOG-rank test, *MICE, *BIOINFORMATICS, *CELL culture, *PROTEOMICS, *WESTERN immunoblotting, *ANIMAL experimentation, *ONE-way analysis of variance, *STATISTICS, *LUNG cancer, *GENETIC techniques, *PROGRESSION-free survival, *STAINS & staining (Microscopy), *DATA analysis software, *OVERALL survival, *RABBITS, *EVALUATION
Abstract: Simple Summary: Lung adenocarcinoma, the most common and deadly form of lung cancer, urgently needs better treatment options and ways to predict patient outcomes. Our research discovers that two specific proteins in cancer cells—one that handles copper (ATOX1) and another that controls cell movement (ROCK1)—work together to drive cancer growth. When we studied over 500 patient samples, we found that patients with low levels of both proteins had significantly better survival rates. In laboratory experiments, simultaneously blocking both proteins reduced cancer cell growth by more than half and dramatically slowed their ability to spread. Remarkably, when tested in mice with lung tumours, drugs targeting both proteins shrank tumours nearly twice as effectively as either drug alone. These findings provide two important benefits: doctors can use measurements of these proteins to identify high-risk patients, and new combination therapies simultaneously blocking both targets could significantly improve survival for lung cancer patients—potentially offering new hope where current treatments often fail. Background: Lung adenocarcinoma (LUAD), the most prevalent and malignant form of lung cancer subtypes, is in urgent need of additional therapeutic targets and prognostic indicators. Antioxidant 1 (ATOX1) copper chaperone and RhoA/Rho kinase 1 (ROCK1) are novel anti-tumour targets in cancers. However, their prognostic value and synergistic inhibitory effect remain unclear in LUAD. Methods: We re-analyzed the open-access proteomic landscape study of LUAD in 2019 and investigated the prognostic value of ATOX1/ROCK1 expression patterns. Then we verified it immunohistochemically using an independent cohort from our hospital enrolling 35 patients with TNM stage III/IV LUAD. In vitro, double fluorescence was used to confirm the co-expression and location of ATOX1/ROCK1. The CCK—8 assay and Transwell assay were carried out to assess the changes in proliferation and migration of Lewis lung carcinoma (LLC) cells following treatment with ATOX1/ROCK1 si-RNA or inhibitory drugs. Western blot was used to confirm protein expression after si-RNA transfection. Moreover, ATOX1/ROCK1-targeted drugs' therapeutic effects were further investigated in the LLC allogeneic transplantation model and MNU-induced tumour model. Results: Firstly, according to the ATOX1/ROCK1 expression pattern derived from proteomic data, double-low expression of ATOX1/ROCK1 indicated a better Disease Free Survival (DFS) (log-rank test p = 0.01) and Overall Survival (OS) (log-rank test p = 8.2 × 10−3), whose expression was also correlated with the lower expression of MCM family proteins. Further, we verified this prognostic correlation in our cohort. The IHC-defined ATOX1/ROCK1 low subtype also had the best OS (log-rank test p = 2.4 × 10−3). In vitro, double fluorescence confirmed that ATOX1/ROCK1 was highly expressed together in Lewis cells. Co-inhibition of ATOX1 and ROCK1 either by siRNA transfection or inhibitory drugs could lead to a significant decrease in tumour proliferation. Interestingly, transcriptional inhibition of ATOX1 can lead to the up-regulation of ROCK1, while inhibition of ROCK1 resulted in the promotion of ATOX1. Moreover, in the analysis of migration ability, a similar synergistic effect from the co-inhibition of ATOX1/ROCK1 was also observed. Finally, the Lewis and Mnu-induced allogeneic transplantation model also demonstrated a greatly improved therapeutic effect by combining targeting ATOX1 and ROCK1. Conclusions: Collectively, our results suggest that a low expression pattern of ATOX1/ROCK1 can predict better clinical outcomes in LUAD. Combining the inhibition of these two targets can reach a significantly better therapeutic effect than targeting either alone. [ABSTRACT FROM AUTHOR]
Datenbank: Academic Search Index
Beschreibung
Abstract:Simple Summary: Lung adenocarcinoma, the most common and deadly form of lung cancer, urgently needs better treatment options and ways to predict patient outcomes. Our research discovers that two specific proteins in cancer cells—one that handles copper (ATOX1) and another that controls cell movement (ROCK1)—work together to drive cancer growth. When we studied over 500 patient samples, we found that patients with low levels of both proteins had significantly better survival rates. In laboratory experiments, simultaneously blocking both proteins reduced cancer cell growth by more than half and dramatically slowed their ability to spread. Remarkably, when tested in mice with lung tumours, drugs targeting both proteins shrank tumours nearly twice as effectively as either drug alone. These findings provide two important benefits: doctors can use measurements of these proteins to identify high-risk patients, and new combination therapies simultaneously blocking both targets could significantly improve survival for lung cancer patients—potentially offering new hope where current treatments often fail. Background: Lung adenocarcinoma (LUAD), the most prevalent and malignant form of lung cancer subtypes, is in urgent need of additional therapeutic targets and prognostic indicators. Antioxidant 1 (ATOX1) copper chaperone and RhoA/Rho kinase 1 (ROCK1) are novel anti-tumour targets in cancers. However, their prognostic value and synergistic inhibitory effect remain unclear in LUAD. Methods: We re-analyzed the open-access proteomic landscape study of LUAD in 2019 and investigated the prognostic value of ATOX1/ROCK1 expression patterns. Then we verified it immunohistochemically using an independent cohort from our hospital enrolling 35 patients with TNM stage III/IV LUAD. In vitro, double fluorescence was used to confirm the co-expression and location of ATOX1/ROCK1. The CCK—8 assay and Transwell assay were carried out to assess the changes in proliferation and migration of Lewis lung carcinoma (LLC) cells following treatment with ATOX1/ROCK1 si-RNA or inhibitory drugs. Western blot was used to confirm protein expression after si-RNA transfection. Moreover, ATOX1/ROCK1-targeted drugs' therapeutic effects were further investigated in the LLC allogeneic transplantation model and MNU-induced tumour model. Results: Firstly, according to the ATOX1/ROCK1 expression pattern derived from proteomic data, double-low expression of ATOX1/ROCK1 indicated a better Disease Free Survival (DFS) (log-rank test p = 0.01) and Overall Survival (OS) (log-rank test p = 8.2 × 10−3), whose expression was also correlated with the lower expression of MCM family proteins. Further, we verified this prognostic correlation in our cohort. The IHC-defined ATOX1/ROCK1 low subtype also had the best OS (log-rank test p = 2.4 × 10−3). In vitro, double fluorescence confirmed that ATOX1/ROCK1 was highly expressed together in Lewis cells. Co-inhibition of ATOX1 and ROCK1 either by siRNA transfection or inhibitory drugs could lead to a significant decrease in tumour proliferation. Interestingly, transcriptional inhibition of ATOX1 can lead to the up-regulation of ROCK1, while inhibition of ROCK1 resulted in the promotion of ATOX1. Moreover, in the analysis of migration ability, a similar synergistic effect from the co-inhibition of ATOX1/ROCK1 was also observed. Finally, the Lewis and Mnu-induced allogeneic transplantation model also demonstrated a greatly improved therapeutic effect by combining targeting ATOX1 and ROCK1. Conclusions: Collectively, our results suggest that a low expression pattern of ATOX1/ROCK1 can predict better clinical outcomes in LUAD. Combining the inhibition of these two targets can reach a significantly better therapeutic effect than targeting either alone. [ABSTRACT FROM AUTHOR]
ISSN:20726694
DOI:10.3390/cancers17172887