α-Catulin promotes cancer stemness by antagonizing WWP1-mediated KLF5 degradation in lung cancer

Tung, Chia-Hao; Huang, Meng; Liang, Chen-Hsien; Wu, Yi-Ying; Wu, Jia-En; Hsu, Cheng–Lung; Chen, Yuh-Ling; Hong, Tse-Ming

doi:10.7150/thno.63627

Cited by 12 publications

(10 citation statements)

References 51 publications

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“…Unexpectedly, lorlatinib and DS-6051b almost completely inhibited ADK-VR2 3D-growth, resulting even more effective than crizotinib in these culture conditions (P<0.05 by unpaired t- test with Welch’s correction). The growth of cells in non-adherent conditions is a label of aggressiveness together with the capability to produce spheres, which is considered as an index of stemness ( 24 , 25 ). The ability of a drug to inhibit stem cell proliferation is a valuable aspect, since cancer stemness is frequently associated with cancer progression, survival and response to treatments ( 26 , 27 ).…”

Section: Resultsmentioning

confidence: 99%

ADK-VR2, a cell line derived from a treatment-naïve patient with SDC4-ROS1 fusion-positive primarily crizotinib-resistant NSCLC: a novel preclinical model for new drug development of ROS1-rearranged NSCLC

Ruzzi¹,

Angelicola²,

Landuzzi³

et al. 2022

Transl Lung Cancer Res

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Background: ROS1 fusions are driver molecular alterations in 1-2% of non-small cell lung cancers (NSCLCs). Several tyrosine kinase inhibitors (TKIs) have shown high efficacy in patients whose tumors harbour a ROS1 fusion. However, the limited availability of preclinical models of ROS1-positive NSCLC hinders the discovery of new drugs and the understanding of the mechanisms underlying drug resistance and strategies to overcome it. Methods:The ADK-VR2 cell line was derived from the pleural effusion of a treatment-naïve NSCLC patient bearing SDC4-ROS1 gene fusion. The sensitivity of ADK-VR2 and its crizotinib-resistant clone ADK-VR2 AG143 (selected in 3D culture in the presence of crizotinib) to different TKIs was tested in vitro, in both 2D and 3D conditions. Tumorigenic and metastatic ability was assessed in highly immunodeficient mice. In addition, crizotinib efficacy on ADK-VR2 was evaluated in vivo.Results: 2D-growth of ADK-VR2 cells was partially inhibited by crizotinib. On the contrary, the treatment with other TKIs, such as lorlatinib, entrectinib and DS-6051b, did not result in cell growth inhibition. TKIs showed dramatically different efficacy on ADK-VR2 cells, depending on the cell culture conditions. In 3D culture, ADK-VR2 growth was indeed almost totally inhibited by lorlatinib and DS-6051b. The clone ADK-VR2 AG143 showed higher resistance to crizotinib treatment in vitro, compared to its parental cell line, in both 2D and 3D cultures. Similarly to ADK-VR2, ADK-VR2 AG143 growth was strongly inhibited by ^ ORCID: 0000-0001-6105-4895. lorlatinib in 3D conditions. Nevertheless, ADK-VR2 AG143 sphere formation was less affected by TKIs treatment, compared to the parental cell line. In vivo experiments highlighted the high tumorigenic and metastatic ability of ADK-VR2 cell line, which, once injected in immunodeficient mice, gave rise to both spontaneous and experimental lung metastases while the crizotinib-resistant clone ADK-VR2 AG143 showed a slower growth in vivo. In addition, ADK-VR2 tumor growth was significantly reduced but not eradicated by crizotinib treatment. Conclusions:The ADK-VR2 cell line is a promising NSCLC preclinical model for the study of novel targeted therapies against ROS1 fusions and the mechanisms of resistance to TKI therapies.

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Section: Resultsmentioning

confidence: 99%

ADK-VR2, a cell line derived from a treatment-naïve patient with SDC4-ROS1 fusion-positive primarily crizotinib-resistant NSCLC: a novel preclinical model for new drug development of ROS1-rearranged NSCLC

Ruzzi¹,

Angelicola²,

Landuzzi³

et al. 2022

Transl Lung Cancer Res

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“…Specifically, the expression levels of KLF5 are abnormally elevated in lung cancer tissues, indicating that KLF5 is an oncogene in lung cancer ( 18 ). Furthermore, α-Catulin has been reported to promote cancer stemness by antagonizing the WW domain-containing E3 ubiquitin protein ligase 1-mediated degradation of KLF5 in lung cancer ( 19 ). Testis development-related 1 serves a carcinogenic role in non-small cell lung cancer by targeting the microRNA (miR)-214-5p/KLF5 axis ( 20 ).…”

Section: Discussionmentioning

confidence: 99%

Britannin inhibits cell proliferation, migration and glycolysis by downregulating KLF5 in lung cancer

Wang,

Yu,

et al. 2024

Exp Ther Med

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Lung cancer is a harmful type of malignancy and the leading cause of cancer-associated mortality. It is therefore imperative to develop novel drugs effective for treating this cancer. The Traditional Chinese Medicine compound Britannin has been previously reported to inhibit the development of certain cancers, such as pancreatic, breast and liver cancer. Moreover, Kruppel-like factor 5 (KLF5) has been identified an on oncogene in lung cancer. In the present study, the possible regulatory effects and underlying mechanism of Britannin in lung cancer were investigated. A549 and 16HBE cells were treated with different concentrations of Britannin. Subsequently, Cell counting kit-8, EdU staining and colony formation assays were used to detect the proliferative ability of these cells. Cell migration was detected by wound healing and Transwell assays, respectively. XF96 extracellular flux analyzer was used to analyze the extent of extracellular acidification and oxygen consumption rate in cells, whereas assay kits were used to detect glucose and lactic acid levels in the cell supernatant. The targeting effect between Britannin and the KLF5 protein was investigated using molecular docking technology. The protein expression levels of KLF5 in cells challenged with Britannin was detected by western blotting. Finally, overexpression of KLF5 in A549 cells was performed before cell proliferation, migration and the glycolysis rate were measured to explore the regulatory effects of Britannin. Britannin was found to inhibit the proliferation, migration and glycolysis of lung cancer cells, during which the protein expression levels of KLF5 were decreased. This suggests that Britannin regulated the expression of KLF5 in A549 cells. Overexpression of KLF5 reversed the inhibitory effects of Britannin on the proliferation, migration and glycolysis in lung cancer cells. In conclusion, these results suggest that Britannin can inhibit cell proliferation, migration and glycolysis by downregulating KLF5 expression in lung cancer cells.

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“…Most LUAD patients die of cancer metastasis and treatment resistance [ 56 ]. Cancer stem cells possess the abilities of normal stem cells, especially drug resistance, metastasis, immune escape, etc.…”

Section: Discussionmentioning

confidence: 99%

Definition of a Novel Cuproptosis-Relevant lncRNA Signature for Uncovering Distinct Survival, Genomic Alterations, and Treatment Implications in Lung Adenocarcinoma

Wang

Yao

Dong

et al. 2022

Journal of Immunology Research

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Objective. Cuproptosis is a newly discovered copper-independent cell death modality, and limited evidence suggests the critical implications in human cancers. Nonetheless, the clinical impacts of cuproptosis-relevant lncRNAs in lung adenocarcinoma (LUAD) remain largely ill-defined. The present study was aimed at defining a cuproptosis-relevant lncRNA signature for LUAD and discuss the clinical utility. Methods. We collected transcriptome expression profiling, clinical information, somatic mutation, and copy number variations from TCGA-LUAD cohort retrospectively. The genetic alterations of cuproptosis genes were systematically assessed across LUAD, and cuproptosis-relevant lncRNAs were screened for defining a LASSO prognostic model. Genomic alterations, immunological and stemness features, and therapeutic sensitivity were studied with a series of computational approaches. Results. Cuproptosis genes displayed aberrant expression and widespread genomic alterations across LUAD, potentially modulated by m6A/m5C/m1A RNA modification mechanisms. We defined a cuproptosis-relevant lncRNA signature, with a reliable efficacy in predicting clinical outcomes. High-risk subset displayed higher somatic mutations, CNVs, TMB, SNV neoantigens, aneuploidy score, CTA score, homologous recombination defects, and intratumor heterogeneity, cytolytic activity, CD8+ T effector, and antigen processing machinery, proving that this subset might benefit from immunotherapy. Increased stemness indexes and activity of oncogenic pathways might contribute to undesirable prognostic outcomes for high-risk subset. Additionally, high-risk patients generally exhibited higher response to chemotherapeutic agents (cisplatin, etc.). We also predicted several small molecule compounds (GSK461364, KX2-391, etc.) for treating this subset. Conclusion. Accordingly, this cuproptosis-relevant lncRNA signature offers an efficient approach to identify and characterize diverse prognosis, genomic alterations, and treatment outcomes in LUAD, thus potentially assisting personalized therapy.

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α-Catulin promotes cancer stemness by antagonizing WWP1-mediated KLF5 degradation in lung cancer

Cited by 12 publications

References 51 publications

ADK-VR2, a cell line derived from a treatment-naïve patient with SDC4-ROS1 fusion-positive primarily crizotinib-resistant NSCLC: a novel preclinical model for new drug development of ROS1-rearranged NSCLC

ADK-VR2, a cell line derived from a treatment-naïve patient with SDC4-ROS1 fusion-positive primarily crizotinib-resistant NSCLC: a novel preclinical model for new drug development of ROS1-rearranged NSCLC

Britannin inhibits cell proliferation, migration and glycolysis by downregulating KLF5 in lung cancer

Definition of a Novel Cuproptosis-Relevant lncRNA Signature for Uncovering Distinct Survival, Genomic Alterations, and Treatment Implications in Lung Adenocarcinoma

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