title: Salinomycin inhibits growth of pancreatic cancer and cancer cell migration by disruption of actin stress fiber integrity.
abstract: Pancreatic ductal adenocarcinoma (PDAC) is characterized by aggressive growth, early metastasis and high resistance to chemotherapy. Salinomycin is a promising compound eliminating cancer stem cells and retarding cancer cell migration. The present study investigated the effectiveness of salinomycin against PDAC in vivo and elucidated the mechanism of PDAC growth inhibition. Salinomycin treatment was well tolerated by the mice and significantly reduced tumor growth after 19 days compared to the control group (each n = 16). There was a trend that salinomycin also impeded metastatic spread to the liver and peritoneum. Whereas salinomycin moderately induced apoptosis and retarded proliferation at 5-10 µM, it strongly inhibited cancer cell migration that was accompanied by a marked loss of actin stress fibers after 6-9 h. Salinomycin silenced RhoA activity, and loss of stress fibers could be reversed by Rho activation. Moreover, salinomycin dislocated fascin from filopodia and stimulated Rac-associated circular dorsal ruffle formation. In conclusion, salinomycin is an effective and promising compound against PDAC. Besides its known stem cell-specific cytotoxic effects, salinomycin blocks cancer cell migration by disrupting stress fiber integrity and affecting the mutual Rho-GTPase balance.
authors.affiliation: Department of General, Visceral and Transplantation Surgery, University of Heidelberg, 69120 Heidelberg, Germany.
authors.forename: Miriam
authors.initials: M
authors.lastname: Schenk
authors.affiliation: Department of General, Visceral and Transplantation Surgery, University of Heidelberg, 69120 Heidelberg, Germany.
authors.forename: Berk
authors.initials: B
authors.lastname: Aykut
authors.affiliation: Department of Visceral, Thoracic and Vascular Surgery, University Hospital Carl Gustav Carus, TU Dresden, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Teske
authors.affiliation: Department of General, Visceral and Transplantation Surgery, University of Heidelberg, 69120 Heidelberg, Germany.
authors.forename: Nathalia A
authors.initials: NA
authors.lastname: Giese
authors.affiliation: Department of Visceral, Thoracic and Vascular Surgery, University Hospital Carl Gustav Carus, TU Dresden, Germany.
authors.forename: Juergen
authors.initials: J
authors.lastname: Weitz
authors.affiliation: Department of General, Visceral and Transplantation Surgery, University of Heidelberg, 69120 Heidelberg, Germany; Department of Visceral, Thoracic and Vascular Surgery, University Hospital Carl Gustav Carus, TU Dresden, Germany. Electronic address: thilo.welsch@uniklinikum-dresden.de.
authors.forename: Thilo
authors.initials: T
authors.lastname: Welsch
mesh_terms: D000199:Actins / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D021441:Carcinoma, Pancreatic Ductal / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects; D006801:Humans; D051379:Mice; D009362:Neoplasm Metastasis; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D011714:Pyrans / Q000494:pharmacology*; D022502:Stress Fibers / Q000378:metabolism*; D047368:Tumor Burden / Q000187:drug effects; D020742:rhoA GTP-Binding Protein / Q000378:metabolism; D000095662:Polyether Polyketides
chemical_list: D000199:Actins; D011714:Pyrans; D020742:rhoA GTP-Binding Protein; C010327:salinomycin; D000095662:Polyether Polyketides
keywords: Migration; Pancreatic cancer; RhoA; Salinomycin; Stress fibers