Qi Sun, Xiansong Yang, Ye Wang, Kejia Yang, Yuan Weng
{"title":"NAT10敲低通过抑制TRIM44/PI3K/AKT通路提高非小细胞肺癌顺铂敏感性","authors":"Qi Sun, Xiansong Yang, Ye Wang, Kejia Yang, Yuan Weng","doi":"10.1111/1759-7714.70079","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>Non-small cell lung cancer (NSCLC) is a leading cause of cancer-related deaths worldwide, and cisplatin (DDP) resistance remains a significant challenge in NSCLC treatment.</p><p><strong>Methods: </strong>Quantitative reverse transcription polymerase chain reaction (qRT-PCR) was used to analyze NAT10 and tripartite motif containing 44 (TRIM44) mRNA levels. Western blotting assay was used to detect protein expression. Cell viability was analyzed by a cell counting kit-8 assay. Cell proliferation, apoptosis, invasion, and stem-like traits were assessed using a 5-Ethynyl-2'-deoxyuridineassay, flow cytometry, Transwell invasion assay, and sphere formation assay, respectively. The association between NAT10 and TRIM44 was identified by an RNA immunoprecipitation assay. A xenograft mouse model was established to evaluate the effect of NAT10 silencing on DDP sensitivity in vivo.</p><p><strong>Results: </strong>NAT10 expression was upregulated in DDP-resistant NSCLC tissues and cells. NAT10 knockdown enhanced DDP sensitivity in DDP-resistant NSCLC cells, accompanied by decreased protein expression of multidrug resistance 1 (MDR1). The silencing of NAT10 also inhibited the proliferation, invasion, and stem-like traits of DDP-resistant NSCLC cells, while inducing cell apoptosis. However, NAT10 overexpression displayed the opposite effects. Moreover, NAT10 maintained TRIM44 mRNA stability in an ac4C-dependent manner. TRIM44 overexpression reversed the NAT10 knockdown-induced effects on DDP sensitivity and the malignant progression of NSCLC cells. In addition, NAT10 silencing inactivated the PI3K/AKT pathway by regulating TRIM44 in DDP-resistant NSCLC cells. The treatment of the PI3K/AKT pathway inhibitor, LY294002, mitigated the effects of TRIM44 overexpression on DDP sensitivity and NSCLC cell progression. Further, NAT10 knockdown improved the sensitivity of tumors to DDP in vivo.</p><p><strong>Conclusion: </strong>NAT10 knockdown improved DDP sensitivity in NSCLC by inhibiting the TRIM44/PI3K/AKT pathway, which may have significant clinical implications for overcoming DDP resistance in NSCLC treatment.</p>","PeriodicalId":23338,"journal":{"name":"Thoracic Cancer","volume":"16 9","pages":"e70079"},"PeriodicalIF":2.3000,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12052513/pdf/","citationCount":"0","resultStr":"{\"title\":\"NAT10 Knockdown Improves Cisplatin Sensitivity in Non-Small Cell Lung Cancer by Inhibiting the TRIM44/PI3K/AKT Pathway.\",\"authors\":\"Qi Sun, Xiansong Yang, Ye Wang, Kejia Yang, Yuan Weng\",\"doi\":\"10.1111/1759-7714.70079\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Background: </strong>Non-small cell lung cancer (NSCLC) is a leading cause of cancer-related deaths worldwide, and cisplatin (DDP) resistance remains a significant challenge in NSCLC treatment.</p><p><strong>Methods: </strong>Quantitative reverse transcription polymerase chain reaction (qRT-PCR) was used to analyze NAT10 and tripartite motif containing 44 (TRIM44) mRNA levels. Western blotting assay was used to detect protein expression. Cell viability was analyzed by a cell counting kit-8 assay. Cell proliferation, apoptosis, invasion, and stem-like traits were assessed using a 5-Ethynyl-2'-deoxyuridineassay, flow cytometry, Transwell invasion assay, and sphere formation assay, respectively. The association between NAT10 and TRIM44 was identified by an RNA immunoprecipitation assay. A xenograft mouse model was established to evaluate the effect of NAT10 silencing on DDP sensitivity in vivo.</p><p><strong>Results: </strong>NAT10 expression was upregulated in DDP-resistant NSCLC tissues and cells. NAT10 knockdown enhanced DDP sensitivity in DDP-resistant NSCLC cells, accompanied by decreased protein expression of multidrug resistance 1 (MDR1). The silencing of NAT10 also inhibited the proliferation, invasion, and stem-like traits of DDP-resistant NSCLC cells, while inducing cell apoptosis. However, NAT10 overexpression displayed the opposite effects. Moreover, NAT10 maintained TRIM44 mRNA stability in an ac4C-dependent manner. TRIM44 overexpression reversed the NAT10 knockdown-induced effects on DDP sensitivity and the malignant progression of NSCLC cells. In addition, NAT10 silencing inactivated the PI3K/AKT pathway by regulating TRIM44 in DDP-resistant NSCLC cells. The treatment of the PI3K/AKT pathway inhibitor, LY294002, mitigated the effects of TRIM44 overexpression on DDP sensitivity and NSCLC cell progression. Further, NAT10 knockdown improved the sensitivity of tumors to DDP in vivo.</p><p><strong>Conclusion: </strong>NAT10 knockdown improved DDP sensitivity in NSCLC by inhibiting the TRIM44/PI3K/AKT pathway, which may have significant clinical implications for overcoming DDP resistance in NSCLC treatment.</p>\",\"PeriodicalId\":23338,\"journal\":{\"name\":\"Thoracic Cancer\",\"volume\":\"16 9\",\"pages\":\"e70079\"},\"PeriodicalIF\":2.3000,\"publicationDate\":\"2025-05-01\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12052513/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Thoracic Cancer\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1111/1759-7714.70079\",\"RegionNum\":3,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q3\",\"JCRName\":\"ONCOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Thoracic Cancer","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1111/1759-7714.70079","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q3","JCRName":"ONCOLOGY","Score":null,"Total":0}
NAT10 Knockdown Improves Cisplatin Sensitivity in Non-Small Cell Lung Cancer by Inhibiting the TRIM44/PI3K/AKT Pathway.
Background: Non-small cell lung cancer (NSCLC) is a leading cause of cancer-related deaths worldwide, and cisplatin (DDP) resistance remains a significant challenge in NSCLC treatment.
Methods: Quantitative reverse transcription polymerase chain reaction (qRT-PCR) was used to analyze NAT10 and tripartite motif containing 44 (TRIM44) mRNA levels. Western blotting assay was used to detect protein expression. Cell viability was analyzed by a cell counting kit-8 assay. Cell proliferation, apoptosis, invasion, and stem-like traits were assessed using a 5-Ethynyl-2'-deoxyuridineassay, flow cytometry, Transwell invasion assay, and sphere formation assay, respectively. The association between NAT10 and TRIM44 was identified by an RNA immunoprecipitation assay. A xenograft mouse model was established to evaluate the effect of NAT10 silencing on DDP sensitivity in vivo.
Results: NAT10 expression was upregulated in DDP-resistant NSCLC tissues and cells. NAT10 knockdown enhanced DDP sensitivity in DDP-resistant NSCLC cells, accompanied by decreased protein expression of multidrug resistance 1 (MDR1). The silencing of NAT10 also inhibited the proliferation, invasion, and stem-like traits of DDP-resistant NSCLC cells, while inducing cell apoptosis. However, NAT10 overexpression displayed the opposite effects. Moreover, NAT10 maintained TRIM44 mRNA stability in an ac4C-dependent manner. TRIM44 overexpression reversed the NAT10 knockdown-induced effects on DDP sensitivity and the malignant progression of NSCLC cells. In addition, NAT10 silencing inactivated the PI3K/AKT pathway by regulating TRIM44 in DDP-resistant NSCLC cells. The treatment of the PI3K/AKT pathway inhibitor, LY294002, mitigated the effects of TRIM44 overexpression on DDP sensitivity and NSCLC cell progression. Further, NAT10 knockdown improved the sensitivity of tumors to DDP in vivo.
Conclusion: NAT10 knockdown improved DDP sensitivity in NSCLC by inhibiting the TRIM44/PI3K/AKT pathway, which may have significant clinical implications for overcoming DDP resistance in NSCLC treatment.
期刊介绍：
Thoracic Cancer aims to facilitate international collaboration and exchange of comprehensive and cutting-edge information on basic, translational, and applied clinical research in lung cancer, esophageal cancer, mediastinal cancer, breast cancer and other thoracic malignancies. Prevention, treatment and research relevant to Asia-Pacific is a focus area, but submissions from all regions are welcomed. The editors encourage contributions relevant to prevention, general thoracic surgery, medical oncology, radiology, radiation medicine, pathology, basic cancer research, as well as epidemiological and translational studies in thoracic cancer. Thoracic Cancer is the official publication of the Chinese Society of Lung Cancer, International Chinese Society of Thoracic Surgery and is endorsed by the Korean Association for the Study of Lung Cancer and the Hong Kong Cancer Therapy Society.
The Journal publishes a range of article types including: Editorials, Invited Reviews, Mini Reviews, Original Articles, Clinical Guidelines, Technological Notes, Imaging in thoracic cancer, Meeting Reports, Case Reports, Letters to the Editor, Commentaries, and Brief Reports.
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