دورية أكاديمية
EVA1A reverses lenvatinib resistance in hepatocellular carcinoma through regulating PI3K/AKT/p53 signaling axis.
| العنوان: | EVA1A reverses lenvatinib resistance in hepatocellular carcinoma through regulating PI3K/AKT/p53 signaling axis. |
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| المؤلفون: | Liu X; School of Basic Medicine, College of Electronic Information, Micro-Nano Technology College, Qingdao University, Qingdao, China., Gao X; School of Basic Medicine, College of Electronic Information, Micro-Nano Technology College, Qingdao University, Qingdao, China., Yang Y; Department of Infectious Diseases, Affiliated Hospital of Qingdao University, Qingdao, China., Yang D; School of Basic Medicine, College of Electronic Information, Micro-Nano Technology College, Qingdao University, Qingdao, China., Guo Q; Clinical Laboratory, Qingdao Central Hospital, University of Health and Rehabilitation Sciences, Qingdao, China., Li L; School of Basic Medicine, College of Electronic Information, Micro-Nano Technology College, Qingdao University, Qingdao, China., Liu S; Department of Clinical Medicine, Qingdao Medical College, Qingdao University, Qingdao, China., Cong W; Department of Clinical Medicine, Qingdao Medical College, Qingdao University, Qingdao, China., Lu S; Department of Medical Laboratory, Qingdao Medical College, Qingdao University, Qingdao, China., Hou L; School of Basic Medicine, College of Electronic Information, Micro-Nano Technology College, Qingdao University, Qingdao, China., Wang B; School of Basic Medicine, College of Electronic Information, Micro-Nano Technology College, Qingdao University, Qingdao, China., Li N; School of Basic Medicine, College of Electronic Information, Micro-Nano Technology College, Qingdao University, Qingdao, China. ning-99@163.com. |
| المصدر: | Apoptosis : an international journal on programmed cell death [Apoptosis] 2024 Aug; Vol. 29 (7-8), pp. 1161-1184. Date of Electronic Publication: 2024 May 14. |
| نوع المنشور: | Journal Article |
| اللغة: | English |
| بيانات الدورية: | Publisher: Springer Country of Publication: Netherlands NLM ID: 9712129 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1573-675X (Electronic) Linking ISSN: 13608185 NLM ISO Abbreviation: Apoptosis Subsets: MEDLINE |
| أسماء مطبوعة: | Publication: 2005- : Dordrecht, Netherlands : Springer Original Publication: London : Rapid Science Publishers, |
| مواضيع طبية MeSH: | Carcinoma, Hepatocellular*/drug therapy , Carcinoma, Hepatocellular*/genetics , Carcinoma, Hepatocellular*/metabolism , Carcinoma, Hepatocellular*/pathology , Quinolines*/pharmacology , Quinolines*/therapeutic use , Liver Neoplasms*/drug therapy , Liver Neoplasms*/genetics , Liver Neoplasms*/metabolism , Liver Neoplasms*/pathology , Phenylurea Compounds*/pharmacology , Phenylurea Compounds*/therapeutic use , Drug Resistance, Neoplasm*/genetics , Drug Resistance, Neoplasm*/drug effects , Tumor Suppressor Protein p53*/metabolism , Tumor Suppressor Protein p53*/genetics , Phosphatidylinositol 3-Kinases*/metabolism , Phosphatidylinositol 3-Kinases*/genetics , Signal Transduction*/drug effects , Proto-Oncogene Proteins c-akt*/metabolism , Proto-Oncogene Proteins c-akt*/genetics, Humans ; Animals ; Cell Line, Tumor ; Mice ; Apoptosis/drug effects ; Cell Proliferation/drug effects ; Mice, Nude ; Antineoplastic Agents/pharmacology ; Antineoplastic Agents/therapeutic use ; Gene Expression Regulation, Neoplastic/drug effects ; Male ; Xenograft Model Antitumor Assays ; Mice, Inbred BALB C ; Proto-Oncogene Proteins c-mdm2/metabolism ; Proto-Oncogene Proteins c-mdm2/genetics ; Female |
| مستخلص: | Lenvatinib is a commonly used first-line drug for the treatment of advanced hepatocellular carcinoma (HCC). However, its clinical efficacy is limited due to the drug resistance. EVA1A was a newly identified tumor suppressor, nevertheless, the impact of EVA1A on resistance to lenvatinib treatment in HCC and the potential molecular mechanisms remain unknown. In this study, the expression of EVA1A in HCC lenvatinib-resistant cells is decreased and its low expression was associated with a poor prognosis of HCC. Overexpression of EVA1A reversed lenvatinib resistance in vitro and in vivo, as demonstrated by its ability to promote cell apoptosis and inhibit cell proliferation, invasion, migration, EMT, and tumor growth. Silencing EVA1A in lenvatinib-sensitive parental HCC cells exerted the opposite effect and induced resistance to lenvatinib. Mechanistically, upregulated EVA1A inhibited the PI3K/AKT/MDM2 signaling pathway, resulting in a reduced interaction between MDM2 and p53, thereby stabilizing p53 and enhancing its antitumor activity. In addition, upregulated EVA1A suppressed the PI3K/AKT/mTOR signaling pathway and promoted autophagy, leading to the degradation of mutant p53 and attenuating its oncogenic impact. On the contrary, loss of EVA1A activated the PI3K/AKT/MDM2 signaling pathway and inhibited autophagy, promoting p53 proteasomal degradation and mutant p53 accumulation respectively. These findings establish a crucial role of EVA1A loss in driving lenvatinib resistance involving a mechanism of modulating PI3K/AKT/p53 signaling axis and suggest that upregulating EVA1A is a promising therapeutic strategy for alleviating resistance to lenvatinib, thereby improving the efficacy of HCC treatment. (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.) |
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| فهرسة مساهمة: | Keywords: AKT; Autophagy; Drug resistance; EVA1A; Hepatocellular carcinoma; Lenvatinib; MDM2; p53 |
| المشرفين على المادة: | EE083865G2 (lenvatinib) 0 (Quinolines) 0 (Phenylurea Compounds) 0 (Tumor Suppressor Protein p53) EC 2.7.1.- (Phosphatidylinositol 3-Kinases) EC 2.7.11.1 (Proto-Oncogene Proteins c-akt) 0 (Antineoplastic Agents) 0 (TP53 protein, human) EC 2.3.2.27 (Proto-Oncogene Proteins c-mdm2) |
| تواريخ الأحداث: | Date Created: 20240514 Date Completed: 20240722 Latest Revision: 20240722 |
| رمز التحديث: | 20240722 |
| DOI: | 10.1007/s10495-024-01967-0 |
| PMID: | 38743191 |
| قاعدة البيانات: | MEDLINE |
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| DOI: | 10.1007/s10495-024-01967-0 |