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Monitoring of autophagy is complicated: Salinomycin as an example
Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.ORCID iD: 0000-0001-6105-1213
Department of Medicine/Infectious Diseases, Case Western Reserve University, Cleveland, USA.
Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences. Pomeranian Medical University, Poland.ORCID iD: 0000-0001-9518-1411
2015 (English)In: Biochimica et Biophysica Acta. Molecular Cell Research, ISSN 0167-4889, E-ISSN 1879-2596, ISSN 0167-4889, Vol. 1853, no 3, 604-610 p.Article in journal (Refereed) Published
Abstract [en]

Monitoring of autophagy is challenging because of its multiple steps and lack of single befitting technique for a complete mechanistic understanding, which makes the task complicated. Here, we evaluate the functionality of autophagy triggered by salinomycin (anti-cancer stem cell agent) using flow cytometry and advanced microscopy. We show that salinomycin does induce functional autophagy at lower concentrations and such a dose is cell type-dependent. For example, PC3 cells show active autophagic flux at 10μM concentration of salinomycin while murine embryonic fibroblasts already show an inhibition of flux at such doses. A higher concentration of salinomycin (i.e. 30μM) inhibits autophagic flux in both cell types. The data confirms our previous findings that salinomycin is an inducer of autophagy, whereas autophagic flux inhibition is a secondary response.

Place, publisher, year, edition, pages
Elsevier, 2015. Vol. 1853, no 3, 604-610 p.
Keyword [en]
Autophagic flux; GFP-LC3; Salinomycin; Vacuolization; mTandem GFP-RFP LC3; p62/SQSTRM1
National Category
Basic Medicine Cell and Molecular Biology
URN: urn:nbn:se:liu:diva-113565DOI: 10.1016/j.bbamcr.2014.12.022ISI: 000349878500007PubMedID: 25541282OAI: diva2:783020
Available from: 2015-01-23 Created: 2015-01-23 Last updated: 2016-05-16Bibliographically approved
In thesis
1. Cancer and cancer stem cell targeting agents: A focus on salinomycin and apoptin
Open this publication in new window or tab >>Cancer and cancer stem cell targeting agents: A focus on salinomycin and apoptin
2015 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Current cancer treatments involving surgery, radiotherapy, and chemotherapy target the vast majority of cancer cells, but they are only partially effective in eliminating the disease. Failure to eliminate cancer with conventional treatments can lead to recurrence, which usually kills patient. This often occurs when cancer cells develop resistance to cancer drugs or when cancer-initiating cells (cancer stem cells), unaffected by existing treatment procedures, are present. Here, we studied two drugs, salinomycin and apoptin, that exhibit great potential in the future of cancer treatment not only for restricting malignancy, but also in preventing tumor recurrence. Salinomycin is an antibiotic that was used in poultry farming that is now used clinically to target cancer stem cells, and apoptin is a chicken anemia virus-derived protein that is capable of detecting and killing transformed cells. In this study, we delved into the molecular mechanism of salinomycin action leading to cancer cell death. We showed that salinomycin induces autophagy in both cancer and normal primary cells. We further demonstrated that salinomycin promotes mitochondrial fission, thus increasing mitochondrial mass and mitochondria-specific autophagy, mitophagy. Salinomycin-induced cell death was both necrotic and apoptotic as determined by increased release of HMGB1 and caspase-3, -8 and -9 activation. We also found that stress responses of normal and cancer cells to salinomycin differ and this difference is aggravated by starvation conditions. We proposed that a combinational treatment with glucose starvation, or glucose analogues such as 2DG or 2FDG, might enhance the effects of salinomycin on cancer cells while protecting normal cells. We previously reported that apoptin interacts with BCRABL1, a protein that is expressed in patients with chronic myeloid leukemia (CML). We located a minimal region on the apoptin protein that triggers inhibition of downstream BCR-ABL1 signaling effects. This deca-peptide region was tested on patient samples and was shown to effectively kill cancer cells derived from patients, similar to the drug Imatinib. We further show that the apoptin decapeptide is cytotoxic to Imatinib-resistant patient-derived cancer cells. Thus, we identified a novel therapeutic targeting agent that can not only overcome drug resistance, but it can also induce cancer cell death without affecting normal cells.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2015. 53 p.
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1436
National Category
Basic Medicine Cell and Molecular Biology
urn:nbn:se:liu:diva-113709 (URN)10.3384/diss.diva-113709 (DOI)978-91-7519-153-9 (print) (ISBN)
Public defence
2015-02-26, Berzeliussalen, Campus US, Linköpings universitet, Linköping, 09:00 (English)
Available from: 2015-01-29 Created: 2015-01-29 Last updated: 2015-03-04Bibliographically approved

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