title: Salinomycin induces activation of autophagy, mitophagy and affects mitochondrial polarity: differences between primary and cancer cells.
abstract: The molecular mechanism of Salinomycin's toxicity is not fully understood. Various studies reported that Ca(2+), 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.
authors: Depart. Clinical and Experimental Medicine (IKE), Division of Cell Biology, Linköping Univ., Sweden.
authors: Jaganmohan Reddy
authors: JR
authors: Jangamreddy
authors: Saeid
authors: S
authors: Ghavami
authors: Jerzy
authors: J
authors: Grabarek
authors: Gunnar
authors: G
authors: Kratz
authors: Emilia
authors: E
authors: Wiechec
authors: Bengt-Arne
authors: BA
authors: Fredriksson
authors: Rama Krishna
authors: RK
authors: Rao Pariti
authors: Artur
authors: A
authors: Cieślar-Pobuda
authors: Soumya
authors: S
authors: Panigrahi
authors: Marek J
authors: MJ
authors: Łos
mesh_terms: D000255:Adenosine Triphosphate / Q000235:genetics / Q000378:metabolism; D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D001343:Autophagy / Q000187:drug effects* / Q000235:genetics; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D003603:Cytotoxins / Q000494:pharmacology*; D020405:Dermis / Q000378:metabolism* / Q000473:pathology; D005260:Female; D005347:Fibroblasts / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D008297:Male; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects*; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D063306:Mitophagy / Q000187:drug effects* / Q000235:genetics; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D011714:Pyrans / Q000494:pharmacology*; D060449:Wnt Signaling Pathway / Q000187:drug effects; D000095662:Polyether Polyketides
chemical_list: D000255:Adenosine Triphosphate; D000900:Anti-Bacterial Agents; D003603:Cytotoxins; D011714:Pyrans; C010327:salinomycin; D000095662:Polyether Polyketides