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βIII-tubulin suppression enhances the activity of Amuvatinib to inhibit cell proliferation in c-Met positive non-small cell lung cancer cells.

ABSTRACT: Non-Small Cell Lung Carcinoma (NSCLC) remains a leading cause of cancer death. Resistance to therapy is a significant problem, highlighting the need to find new ways of sensitising tumour cells to therapeutic agents. βIII-tubulin is associated with aggressive tumours and chemotherapy resistance in a range of cancers including NSCLC. βIII-tubulin expression has been shown to impact kinase signalling in NSCLC cells. Here, we sought to exploit this interaction by identifying co-activity between βIII-tubulin suppression and small-molecule kinase inhibitors. To achieve this, a forced-genetics approach combined with a high-throughput drug screen was used. We show that activity of the multi-kinase inhibitor Amuvatinib (MP-470) is enhanced by βIII-tubulin suppression in independent NSCLC cell lines. We also show that this compound significantly inhibits cell proliferation among βIII-tubulin knockdown cells expressing the receptor tyrosine kinase c-Met. Together, our results highlight that βIII-tubulin suppression combined with targeting specific receptor tyrosine kinases may represent a novel therapeutic approach for otherwise difficult-to-treat lung carcinomas.

SUBMITTER: Brayford S

PROVIDER: S-EPMC9972117 | biostudies-literature | 2023 Feb

REPOSITORIES: biostudies-literature

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βIII-tubulin suppression enhances the activity of Amuvatinib to inhibit cell proliferation in c-Met positive non-small cell lung cancer cells.

Brayford Simon S Duly Alastair A Teo Wee Siang WS Dwarte Tanya T Gonzales-Aloy Estrella E Ma Zerong Z McVeigh Laura L Failes Timothy W TW Arndt Greg M GM McCarroll Joshua A JA Kavallaris Maria M

Cancer medicine 20220810 4

Non-Small Cell Lung Carcinoma (NSCLC) remains a leading cause of cancer death. Resistance to therapy is a significant problem, highlighting the need to find new ways of sensitising tumour cells to therapeutic agents. βIII-tubulin is associated with aggressive tumours and chemotherapy resistance in a range of cancers including NSCLC. βIII-tubulin expression has been shown to impact kinase signalling in NSCLC cells. Here, we sought to exploit this interaction by identifying co-activity between βII ...[more]

PMID: 35946957

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Project description:MicroRNA-34a (miR-34a) is a master regulator of signaling networks that maintains normal physiology and disease and is currently in development as a miRNA-based therapy for cancer. Prior studies have reported low miR-34a expression in osteosarcoma; however, the molecular mechanisms underlying miR-34a activity in osteosarcoma are not well-defined. Therefore, this study evaluated the role of miR-34a in regulating signal transduction pathways that influence cell death in osteosarcoma. Levels of miR-34a were attenuated in human osteosarcoma cells and xenografts of the Pediatric Preclinical Testing Consortium (PPTC). Bioinformatics predictions identified stathmin 1 (STMN1) as a potential miR-34a target. Biotin pull-down assay and luciferase reporter analysis confirmed miR-34a target interactions within the STMN1 mRNA 3'-untranslated region. Overexpression of miR-34a in osteosarcoma cells suppressed STMN1 expression and reduced cell growth in vitro Restoration of miR-34a led to microtubule destabilization and increased βIII-tubulin expression, with corresponding G1-G2 phase cell-cycle arrest and apoptosis. Knockdown of the Sp1 transcription factor, by siRNA silencing, also upregulated βIII-tubulin expression in osteosarcoma cells, suggesting that miR-34a indirectly affects Sp1. Validating the coordinating role of miR-34a in microtubule destabilization, when miR-34a was combined with either microtubule inhibitors or chemotherapy, STMN1 phosphorylation was suppressed and there was greater cytotoxicity in osteosarcoma cells. These results demonstrate that miR-34a directly represses STMN1 gene and protein expression and upregulates βIII-tubulin, leading to disruption of the microtubule network and cell death.Implications: The miR-34a/STMN1/βIII-tubulin axis maintains the microtubule cytoskeleton in osteosarcoma, and combining miR-34a with microtubule inhibitors can be investigated as a novel therapeutic strategy. Mol Cancer Res; 15(7); 953-64. ©2017 AACR.

Dataset Information

βIII-tubulin suppression enhances the activity of Amuvatinib to inhibit cell proliferation in c-Met positive non-small cell lung cancer cells.

Publications

βIII-tubulin suppression enhances the activity of Amuvatinib to inhibit cell proliferation in c-Met positive non-small cell lung cancer cells.

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