Back to Search
Start Over
Solamargine enhanced gefitinib antitumor effect via regulating MALAT1/miR-141-3p/Sp1/IGFBP1 signaling pathway in non-small cell lung cancer.
- Source :
-
Carcinogenesis [Carcinogenesis] 2023 Aug 18; Vol. 44 (6), pp. 497-510. - Publication Year :
- 2023
-
Abstract
- Lung cancer is the leading cause of cancer-related deaths worldwide. Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) showed great therapeutic efficacy for non-small cell lung cancer (NSCLC) patients. However, acquired resistance severely limits the clinical application and efficacy of EGFR-TKIs. In the current study, we found that solamargine (SM), a natural alkaloid derived from the fruit of Lycium tomato lobelia, has been found to inhibit the progression of NSCLC and enhance the anticancer effect of EGFR-TKIs. In brief, SM significantly inhibited the cell viability of NSCLC cells and enhanced the anticancer effect of gefitinib (GFTN) and erlotinib (ERL). Mechanistically, SM decreased the expression of MALAT1 and induced miR-141-3p, whereas reduced SP1 protein levels. Interestingly, both MALAT1 and Sp1 have classical and conservative binding sites of miR-141-3p in their 3'-UTR regions. Silence of MALAT1 and overexpression of miR-141-3p both decreased the protein expression of Sp1. Subsequently, promoter activity and protein expression of IGFBP1 were upregulated by SM, which was not observed in cells with SP1 overexpression. Moreover, the inhibitory effect of SM on cell growth was significantly blocked by knockdown of IGFBP1 expression. More importantly, the combination of SM and GFTN synergistically inhibited the progression of lung cancer. Similar results were observed in experiments in vivo. Finally, the clinical relevance of MALAT1, Sp1 and IGFBP1 was further validated using bioinformatics analysis. Taken together, we confirmed that SM significantly enhanced the anticancer effect of EGFR-TKIs by regulating the MALAT1/miR-141-3p/Sp1/IGFBP1 signaling pathway. This study unravels a novel mechanism and suggests a new potential NSCLC-associated therapy.<br /> (© The Author(s) 2023. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)
- Subjects :
- Humans
Gefitinib pharmacology
Gefitinib therapeutic use
Cell Line, Tumor
Signal Transduction
ErbB Receptors genetics
ErbB Receptors metabolism
Drug Resistance, Neoplasm genetics
Protein Kinase Inhibitors pharmacology
Gene Expression Regulation, Neoplastic
Insulin-Like Growth Factor Binding Protein 1 genetics
Insulin-Like Growth Factor Binding Protein 1 metabolism
Carcinoma, Non-Small-Cell Lung drug therapy
Carcinoma, Non-Small-Cell Lung genetics
Carcinoma, Non-Small-Cell Lung pathology
Lung Neoplasms drug therapy
Lung Neoplasms genetics
Lung Neoplasms pathology
RNA, Long Noncoding genetics
RNA, Long Noncoding metabolism
MicroRNAs genetics
MicroRNAs metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1460-2180
- Volume :
- 44
- Issue :
- 6
- Database :
- MEDLINE
- Journal :
- Carcinogenesis
- Publication Type :
- Academic Journal
- Accession number :
- 37144780
- Full Text :
- https://doi.org/10.1093/carcin/bgad028