Sublethal doxorubicin promotes migration and invasion of breast cancer cells: role of Src Family non-receptor tyrosine kinases.
Background: Doxorubicin (Dox) is a widely used chemotherapy, but its effectiveness is limited by dose-dependent side effects. Although lower Dox doses reduce this risk, studies have reported higher recurrence of local disease with no improvement in survival rate in patients receiving low doses of Do...
| Publicado en: | Breast Cancer Research Vol. 23; no. 1; pp. 1 - 21 |
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| Autores principales: | , , , , , , , , , |
| Formato: | research Journal Article |
| Publicado: |
BioMed Central
7/27/2021
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| Acceso en línea: | Ver este registro en EBSCOhost |
| fields | @attributes: recordID: 1 pdfLink: plink: https://search.ebscohost.com/login.aspx?direct=true&db=ccm&AN=151626887&site=ehost-live header: @attributes: shortDbName: ccm uiTerm: 151626887 longDbName: CINAHL Complete uiTag: AN controlInfo: bkinfo: dissinfo: jinfo: jid: 14655411 8UYJ jtl: Breast Cancer Research issn: 14655411 maglogo: N pubinfo: dt: 7/27/2021 vid: 23 iid: 1 pid: 24147 pub: BioMed Central artinfo: ui: 151626887 151626887 NLM34315513 151626887 10.1186/s13058-021-01452-5 NLM34315513 151626887 ppf: 1 ppct: 20 formats: fmt: – @attributes: type: T – @attributes: type: P tig: atl: Sublethal doxorubicin promotes migration and invasion of breast cancer cells: role of Src Family non-receptor tyrosine kinases. aug: au: Mohammed, Samia Shamseddine, Achraf A. Newcomb, Benjamin Chavez, Ronald S. Panzner, Tyler D. Lee, Allen H. Canals, Daniel Okeoma, Chioma M. Clarke, Christopher J. Hannun, Yusuf A. affil: Department of Biochemistry and Cell Biology, Stony Brook University, 11794- 8430, Stony Brook, NY, USA sug: subj: Cell Movement Drug Effects Doxorubicin Pharmacodynamics Transferases Metabolism Cell Line, Tumor Transferases Antagonists and Inhibitors Cell Physiology Drug Effects Cell Movement Protein Kinase Inhibitors Pharmacodynamics Proteins Metabolism Dose-Response Relationship, Drug Breast Neoplasms Pathology Breast Neoplasms Metabolism Female Breast Neoplasms Drug Therapy Human Protein Kinases Metabolism Cell Physiology Comparative Studies Multicenter Studies Evaluation Research Validation Studies Female ab: Background: Doxorubicin (Dox) is a widely used chemotherapy, but its effectiveness is limited by dose-dependent side effects. Although lower Dox doses reduce this risk, studies have reported higher recurrence of local disease with no improvement in survival rate in patients receiving low doses of Dox. To effectively mitigate this, a better understanding of the adverse effects of suboptimal Dox doses is needed.Methods: Effects of sublethal dose of Dox on phenotypic changes were assessed with light and confocal microscopy. Migratory and invasive behavior were assessed by wound healing and transwell migration assays. MTT and LDH release assays were used to analyze cell growth and cytotoxicity. Flow cytometry was employed to detect cell surface markers of cancer stem cell population. Expression and activity of matrix metalloproteinases were probed with qRT-PCR and zymogen assay. To identify pathways affected by sublethal dose of Dox, exploratory RNAseq was performed and results were verified by qRT-PCR in multiple cell lines (MCF7, ZR75-1 and U-2OS). Regulation of Src Family kinases (SFK) by key players in DNA damage response was assessed by siRNA knockdown along with western blot and qRT-PCR. Dasatinib and siRNA for Fyn and Yes was employed to inhibit SFKs and verify their role in increased migration and invasion in MCF7 cells treated with sublethal doses of Dox.Results: The results show that sublethal Dox treatment leads to increased migration and invasion in otherwise non-invasive MCF7 breast cancer cells. Mechanistically, these effects were independent of the epithelial mesenchymal transition, were not due to increased cancer stem cell population, and were not observed with other chemotherapies. Instead, sublethal Dox induces expression of multiple SFK-including Fyn, Yes, and Src-partly in a p53 and ATR-dependent manner. These effects were validated in multiple cell lines. Functionally, inhibiting SFKs with Dasatinib and specific downregulation of Fyn suppressed Dox-induced migration and invasion of MCF7 cells.Conclusions: Overall, this study demonstrates that sublethal doses of Dox activate a pro-invasive, pro-migration program in cancer cells. Furthermore, by identifying SFKs as key mediators of these effects, our results define a potential therapeutic strategy to mitigate local invasion through co-treatment with Dasatinib. pubtype: Academic Journal doctype: research Journal Article ougenre: Article language: English refInfo: holdings: @attributes: islocal: N |
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