Minxue Gai, Lanlan Zhao, Hongqi Li, Guoyu Jin, Wei Li, Fei Wang, Ming Liu
{"title":"LCP1 通过激活 JAK2/STAT3 信号通路促进卵巢癌细胞对奥拉帕尼的耐药性。","authors":"Minxue Gai, Lanlan Zhao, Hongqi Li, Guoyu Jin, Wei Li, Fei Wang, Ming Liu","doi":"10.1080/15384047.2024.2432117","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>Resistance to poly (ADP-ribose) polymerase (PARP) inhibitors (PARPis) remain a major challenge in ovarian cancer (OC) treatment. However, the underlying mechanism of PARPi resistance is still poorly characterized. Increasing evidence has proven that lymphocyte cytosolic protein 1 (LCP1) promotes tumor progression. The JAK2/STAT3 signaling pathway plays an important role in increasing tumor metastatic ability and chemoresistance in cancer by promoting epithelial - mesenchymal transition (EMT).</p><p><strong>Methods: </strong>We established an olaparib-resistant OC cell line and studied its toxicologic effects through cell survival, Transwell, colony formation, western blotting and flow cytometry assays. RNA sequencing and screening were then performed to identify genes associated with olaparib resistance. Lymphocyte cytosolic protein 1 (LCP1) was found to be overexpressed in olaparib-resistant OC cells.</p><p><strong>Results: </strong>The inhibition of cell survival and promotion of cell apoptosis induced by olaparib in parental cells were significantly attenuated in olaparib-resistant cells. LCP1 was upregulated in olaparib-resistant cells compared with parental OC cells. Moreover, we found that the protein levels of JAK2/STAT3 signaling pathway components and EMT markers were increased in olaparib-resistant cells. Overexpression of LCP1 increased olaparib resistance in OC cells, and knockdown of LCP1 attenuated olaparib resistance. The changes in the protein levels of JAK2/STAT3 signaling pathway members and EMT markers between the cell types were similar to the changes in the levels of LCP1.</p><p><strong>Conclusions: </strong>These findings indicate that LCP1 expression may play an important role in the resistance of OC to olaparib by activating the JAK2/STAT3 signaling pathway and EMT. LCP1 could be a potential therapeutic target for patients with OC who are resistant to olaparib. Our study provides a new mechanism of olaparib resistance.</p>","PeriodicalId":9536,"journal":{"name":"Cancer Biology & Therapy","volume":"25 1","pages":"2432117"},"PeriodicalIF":4.4000,"publicationDate":"2024-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11601053/pdf/","citationCount":"0","resultStr":"{\"title\":\"LCP1 promotes ovarian cancer cell resistance to olaparib by activating the JAK2/STAT3 signalling pathway.\",\"authors\":\"Minxue Gai, Lanlan Zhao, Hongqi Li, Guoyu Jin, Wei Li, Fei Wang, Ming Liu\",\"doi\":\"10.1080/15384047.2024.2432117\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Background: </strong>Resistance to poly (ADP-ribose) polymerase (PARP) inhibitors (PARPis) remain a major challenge in ovarian cancer (OC) treatment. However, the underlying mechanism of PARPi resistance is still poorly characterized. Increasing evidence has proven that lymphocyte cytosolic protein 1 (LCP1) promotes tumor progression. The JAK2/STAT3 signaling pathway plays an important role in increasing tumor metastatic ability and chemoresistance in cancer by promoting epithelial - mesenchymal transition (EMT).</p><p><strong>Methods: </strong>We established an olaparib-resistant OC cell line and studied its toxicologic effects through cell survival, Transwell, colony formation, western blotting and flow cytometry assays. RNA sequencing and screening were then performed to identify genes associated with olaparib resistance. Lymphocyte cytosolic protein 1 (LCP1) was found to be overexpressed in olaparib-resistant OC cells.</p><p><strong>Results: </strong>The inhibition of cell survival and promotion of cell apoptosis induced by olaparib in parental cells were significantly attenuated in olaparib-resistant cells. LCP1 was upregulated in olaparib-resistant cells compared with parental OC cells. Moreover, we found that the protein levels of JAK2/STAT3 signaling pathway components and EMT markers were increased in olaparib-resistant cells. Overexpression of LCP1 increased olaparib resistance in OC cells, and knockdown of LCP1 attenuated olaparib resistance. The changes in the protein levels of JAK2/STAT3 signaling pathway members and EMT markers between the cell types were similar to the changes in the levels of LCP1.</p><p><strong>Conclusions: </strong>These findings indicate that LCP1 expression may play an important role in the resistance of OC to olaparib by activating the JAK2/STAT3 signaling pathway and EMT. LCP1 could be a potential therapeutic target for patients with OC who are resistant to olaparib. Our study provides a new mechanism of olaparib resistance.</p>\",\"PeriodicalId\":9536,\"journal\":{\"name\":\"Cancer Biology & Therapy\",\"volume\":\"25 1\",\"pages\":\"2432117\"},\"PeriodicalIF\":4.4000,\"publicationDate\":\"2024-12-31\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11601053/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Cancer Biology & Therapy\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1080/15384047.2024.2432117\",\"RegionNum\":4,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"2024/11/26 0:00:00\",\"PubModel\":\"Epub\",\"JCR\":\"Q2\",\"JCRName\":\"ONCOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Cancer Biology & Therapy","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1080/15384047.2024.2432117","RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2024/11/26 0:00:00","PubModel":"Epub","JCR":"Q2","JCRName":"ONCOLOGY","Score":null,"Total":0}
LCP1 promotes ovarian cancer cell resistance to olaparib by activating the JAK2/STAT3 signalling pathway.
Background: Resistance to poly (ADP-ribose) polymerase (PARP) inhibitors (PARPis) remain a major challenge in ovarian cancer (OC) treatment. However, the underlying mechanism of PARPi resistance is still poorly characterized. Increasing evidence has proven that lymphocyte cytosolic protein 1 (LCP1) promotes tumor progression. The JAK2/STAT3 signaling pathway plays an important role in increasing tumor metastatic ability and chemoresistance in cancer by promoting epithelial - mesenchymal transition (EMT).
Methods: We established an olaparib-resistant OC cell line and studied its toxicologic effects through cell survival, Transwell, colony formation, western blotting and flow cytometry assays. RNA sequencing and screening were then performed to identify genes associated with olaparib resistance. Lymphocyte cytosolic protein 1 (LCP1) was found to be overexpressed in olaparib-resistant OC cells.
Results: The inhibition of cell survival and promotion of cell apoptosis induced by olaparib in parental cells were significantly attenuated in olaparib-resistant cells. LCP1 was upregulated in olaparib-resistant cells compared with parental OC cells. Moreover, we found that the protein levels of JAK2/STAT3 signaling pathway components and EMT markers were increased in olaparib-resistant cells. Overexpression of LCP1 increased olaparib resistance in OC cells, and knockdown of LCP1 attenuated olaparib resistance. The changes in the protein levels of JAK2/STAT3 signaling pathway members and EMT markers between the cell types were similar to the changes in the levels of LCP1.
Conclusions: These findings indicate that LCP1 expression may play an important role in the resistance of OC to olaparib by activating the JAK2/STAT3 signaling pathway and EMT. LCP1 could be a potential therapeutic target for patients with OC who are resistant to olaparib. Our study provides a new mechanism of olaparib resistance.
期刊介绍：
Cancer, the second leading cause of death, is a heterogenous group of over 100 diseases. Cancer is characterized by disordered and deregulated cellular and stromal proliferation accompanied by reduced cell death with the ability to survive under stresses of nutrient and growth factor deprivation, hypoxia, and loss of cell-to-cell contacts. At the molecular level, cancer is a genetic disease that develops due to the accumulation of mutations over time in somatic cells. The phenotype includes genomic instability and chromosomal aneuploidy that allows for acceleration of genetic change. Malignant transformation and tumor progression of any cell requires immortalization, loss of checkpoint control, deregulation of growth, and survival. A tremendous amount has been learned about the numerous cellular and molecular genetic changes and the host-tumor interactions that accompany tumor development and progression. It is the goal of the field of Molecular Oncology to use this knowledge to understand cancer pathogenesis and drug action, as well as to develop more effective diagnostic and therapeutic strategies for cancer. This includes preventative strategies as well as approaches to treat metastases. With the availability of the human genome sequence and genomic and proteomic approaches, a wealth of tools and resources are generating even more information. The challenge will be to make biological sense out of the information, to develop appropriate models and hypotheses and to translate information for the clinicians and the benefit of their patients. Cancer Biology & Therapy aims to publish original research on the molecular basis of cancer, including articles with translational relevance to diagnosis or therapy. We will include timely reviews covering the broad scope of the journal. The journal will also publish op-ed pieces and meeting reports of interest. The goal is to foster communication and rapid exchange of information through timely publication of important results using traditional as well as electronic formats. The journal and the outstanding Editorial Board will strive to maintain the highest standards for excellence in all activities to generate a valuable resource.
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