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Glucose starvation-mediated inhibition of salinomycin induced autophagy amplifies cancer cell specific cell death
Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences. (Marek Los)ORCID iD: 0000-0001-6105-1213
Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology. Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences.
Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Otorhinolaryngology in Linköping.
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2015 (English)In: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 6, no 12, 10134-10145 p.Article in journal (Refereed) Published
Abstract [en]

Salinomycin has been used as treatment for malignant tumors in a small number of humans, causing far less side effects than standard chemotherapy. Several studies show that Salinomycin targets cancer-initiating cells (cancer stem cells, or CSC) resistant to conventional therapies. Numerous studies show that Salinomycin not only reduces tumor volume, but also decreases tumor recurrence when used as an adjuvant to standard treatments. In this study we show that starvation triggered different stress responses in cancer cells and primary normal cells, which further improved the preferential targeting of cancer cells by Salinomycin. Our in vitro studies further demonstrate that the combined use of 2-Fluoro 2-deoxy D-glucose, or 2-deoxy D-glucose with Salinomycin is lethal in cancer cells while the use of Oxamate does not improve cell death-inducing properties of Salinomycin. Furthermore, we show that treatment of cancer cells with Salinomycin under starvation conditions not only increases the apoptotic caspase activity, but also diminishes the protective autophagy normally triggered by the treatment with Salinomycin alone. Thus, this study underlines the potential use of Salinomycin as a cancer treatment, possibly in combination with short-term starvation or starvation-mimicking pharmacologic intervention.

Place, publisher, year, edition, pages
IMPACT JOURNALS LLC , 2015. Vol. 6, no 12, 10134-10145 p.
Keyword [en]
Glucose starvation, 2DG, 2FDG, Normoxia and Hypoxia, Differential Stress Response, autophagy, Akt, Tricirabine, Salinomycin
National Category
Cell and Molecular Biology
Identifiers
URN: urn:nbn:se:liu:diva-113707ISI: 000358874600039OAI: oai:DiVA.org:liu-113707DiVA: diva2:784349
Available from: 2015-01-29 Created: 2015-01-29 Last updated: 2017-12-05Bibliographically 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.
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1436
National Category
Basic Medicine Cell and Molecular Biology
Identifiers
urn:nbn:se:liu:diva-113709 (URN)10.3384/diss.diva-113709 (DOI)978-91-7519-153-9 (ISBN)
Public defence
2015-02-26, Berzeliussalen, Campus US, Linköpings universitet, Linköping, 09:00 (English)
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Available from: 2015-01-29 Created: 2015-01-29 Last updated: 2015-03-04Bibliographically approved

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Jangamreddy, Jaganmohan ReddyJain, Mayur V.Hallbeck, Anna-LottaRoberg, KarinLotfi, KouroshLos, Marek Jan

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Jangamreddy, Jaganmohan ReddyJain, Mayur V.Hallbeck, Anna-LottaRoberg, KarinLotfi, KouroshLos, Marek Jan
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Division of Cell BiologyFaculty of Health SciencesDepartment of OncologyDivision of Clinical SciencesDivision of Neuro and Inflammation ScienceFaculty of Medicine and Health SciencesDepartment of Otorhinolaryngology in LinköpingDivision of Drug ResearchDepartment of Clinical Pharmacology
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