Change search
ReferencesLink to record
Permanent link

Direct link
Salinomycin induces activation of autophagy, mitophagy and affects mitochondrial polarity: Differences between primary and cancer cells
Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.ORCID iD: 0000-0001-6105-1213
University of Manitoba, Winnipeg, Canada.
Pomeranian Medical University, Szczecin, Poland.
Linköping University, Department of Clinical and Experimental Medicine, Regenerative Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Anaesthetics, Operations and Specialty Surgery Center, Department of Hand and Plastic Surgery.
Show others and affiliations
2013 (English)In: Biochimica et Biophysica Acta. Molecular Cell Research, ISSN 0167-4889, Vol. 1833, no 9, 2057-2069 p.Article in journal (Refereed) Published
Abstract [en]

The molecular mechanism of Salinomycin's toxicity is not fully understood. Various studies reported that Ca2 +, cytochrome c, and caspase activation play a role in Salinomycin-induced cytotoxicity. Furthermore, Salinomycin may target Wnt/β-catenin signaling pathway to promote differentiation and thus elimination of cancer stem cells. In this study, we show a massive autophagic response to Salinomycin (substantially stronger than to commonly used autophagic inducer Rapamycin) in prostrate-, breast cancer cells, and to lesser degree in human normal dermal fibroblasts. Interestingly, autophagy induced by Salinomycin is a cell protective mechanism in all tested cancer cell lines. Furthermore, Salinomycin induces mitophagy, mitoptosis and increased mitochondrial membrane potential (∆Ψ) in a subpopulation of cells. Salinomycin strongly, and in time-dependent manner decreases cellular ATP level. Contrastingly, human normal dermal fibroblasts treated with Salinomycin show some initial decrease in mitochondrial mass, however they are largely resistant to Salinomycin-triggered ATP-depletion. Our data provide new insight into the molecular mechanism of preferential toxicity of Salinomycin towards cancer cells, and suggest possible clinical application of Salinomycin in combination with autophagy inhibitors (i.e. clinically-used Chloroquine). Furthermore, we discuss preferential Salinomycins toxicity in the context of Warburg effect.

Place, publisher, year, edition, pages
2013. Vol. 1833, no 9, 2057-2069 p.
Keyword [en]
cancer stem cells; mitofusin; mitophagy; mTOR; PGC1α; salinomycin
National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
URN: urn:nbn:se:liu:diva-91756DOI: 10.1016/j.bbamcr.2013.04.011ISI: 000321173900004PubMedID: 23639289OAI: diva2:619019
Available from: 2013-05-01 Created: 2013-05-01 Last updated: 2015-01-29
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

Open Access in DiVA

fulltext(2692 kB)714 downloads
File information
File name FULLTEXT01.pdfFile size 2692 kBChecksum SHA-512
Type fulltextMimetype application/pdf

Other links

Publisher's full textPubMed

Search in DiVA

By author/editor
Jangamreddy, JaganmohanKratz, GunnarWiechec, EmiliaFredriksson, Bengt-ArneRao, Rama K.Cieślar-Pobuda, ArturŁos, Marek
By organisation
Cell BiologyFaculty of Health SciencesRegenerative MedicineDepartment of Hand and Plastic Surgery
In the same journal
Biochimica et Biophysica Acta. Molecular Cell Research
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)

Search outside of DiVA

GoogleGoogle Scholar
Total: 714 downloads
The number of downloads is the sum of all downloads of full texts. It may include eg previous versions that are now no longer available

Altmetric score

Total: 191 hits
ReferencesLink to record
Permanent link

Direct link