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Salinomycin induces activation of autophagy, mitophagy and affects mitochondrial polarity: Differences between primary and cancer cells
Linköpings universitet, Institutionen för klinisk och experimentell medicin, Cellbiologi. Linköpings universitet, Hälsouniversitetet.ORCID-id: 0000-0001-6105-1213
University of Manitoba, Winnipeg, Canada.
Pomeranian Medical University, Szczecin, Poland.
Linköpings universitet, Institutionen för klinisk och experimentell medicin, Regenerativ medicin. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Sinnescentrum, Hand- och plastikkirurgiska kliniken US.
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2013 (Engelska)Ingår i: Biochimica et Biophysica Acta. Molecular Cell Research, ISSN 0167-4889, E-ISSN 1879-2596, Vol. 1833, nr 9, s. 2057-2069Artikel i tidskrift (Refereegranskat) 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.

Ort, förlag, år, upplaga, sidor
2013. Vol. 1833, nr 9, s. 2057-2069
Nyckelord [en]
cancer stem cells; mitofusin; mitophagy; mTOR; PGC1α; salinomycin
Nationell ämneskategori
Medicinsk bioteknologi (med inriktning mot cellbiologi (inklusive stamcellsbiologi), molekylärbiologi, mikrobiologi, biokemi eller biofarmaci)
Identifikatorer
URN: urn:nbn:se:liu:diva-91756DOI: 10.1016/j.bbamcr.2013.04.011ISI: 000321173900004PubMedID: 23639289OAI: oai:DiVA.org:liu-91756DiVA, id: diva2:619019
Tillgänglig från: 2013-05-01 Skapad: 2013-05-01 Senast uppdaterad: 2017-12-06
Ingår i avhandling
1. Cancer and cancer stem cell targeting agents: A focus on salinomycin and apoptin
Öppna denna publikation i ny flik eller fönster >>Cancer and cancer stem cell targeting agents: A focus on salinomycin and apoptin
2015 (Engelska)Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
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.

Ort, förlag, år, upplaga, sidor
Linköping: Linköping University Electronic Press, 2015. s. 53
Serie
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1436
Nationell ämneskategori
Medicinska och farmaceutiska grundvetenskaper Cell- och molekylärbiologi
Identifikatorer
urn:nbn:se:liu:diva-113709 (URN)10.3384/diss.diva-113709 (DOI)978-91-7519-153-9 (ISBN)
Disputation
2015-02-26, Berzeliussalen, Campus US, Linköpings universitet, Linköping, 09:00 (Engelska)
Opponent
Handledare
Tillgänglig från: 2015-01-29 Skapad: 2015-01-29 Senast uppdaterad: 2018-01-11Bibliografiskt granskad

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Biochimica et Biophysica Acta. Molecular Cell Research
Medicinsk bioteknologi (med inriktning mot cellbiologi (inklusive stamcellsbiologi), molekylärbiologi, mikrobiologi, biokemi eller biofarmaci)

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