title: The Proteasome Inhibitor Bortezomib Affects Chondrosarcoma Cells via the Mitochondria-Caspase Dependent Pathway and Enhances Death Receptor Expression and Autophagy.
abstract: High grade chondrosarcoma is characterized by its lack of response to conventional cytotoxic chemotherapy, the tendency to develop lung metastases, and low survival rates. Research within the field prioritizes the development and expansion of new treatment options for dealing with unresectable or metastatic diseases. Numerous clinical trials using the proteasome inhibitor bortezomib have shown specific efficacy as an active antitumor agent for treating a variety of solid tumors. However, as of yet the effect of bortezomib on chondrosarcoma has not been investigated. In our study, bortezomib decreased cell viability and proliferation in two different chondrosarcoma cell lines in a time- and dose dependent manner. FACS analysis, mRNA- and protein expression studies illustrated that induction of apoptosis developed through the intrinsic mitochondria-caspase dependent pathway. Furthermore, bortezomib treatment significantly increased expression of the death receptors TRAILR-1 and TRAILR-2 in chondrosarcoma cells. An increased expression of the autophagy markers Atg5/12, Beclin, and LC3BI-II supports the interpretation that bortezomib functions as a trigger for autophagy. Our results demonstrated for the first time that bortezomib reduced viability and proliferation of chondrosarcoma cells, induced apoptosis via the mitochondria-caspase dependent pathway and enhanced death receptor expression and autophagy.
authors.affiliation: Department of Orthopedic Surgery, Medical University Graz, Graz, Austria.
authors.forename: Birgit
authors.initials: B
authors.lastname: Lohberger
authors.affiliation: Ludwig Boltzmann Institute for Rehabilitation of Internal Diseases, Ludwig Boltzmann Cluster for Rheumatology, Balneology and Rehabilitation, Saalfelden, Austria.|Institute of Biophysics, Medical University of Graz, Graz, Austria.
authors.forename: Bibiane
authors.initials: B
authors.lastname: Steinecker-Frohnwieser
authors.affiliation: Department of Orthopedic Surgery, Medical University Graz, Graz, Austria.
authors.forename: Nicole
authors.initials: N
authors.lastname: Stuendl
authors.affiliation: Department of Orthopedic Surgery, Medical University Graz, Graz, Austria.
authors.forename: Heike
authors.initials: H
authors.lastname: Kaltenegger
authors.affiliation: Department of Orthopedic Surgery, Medical University Graz, Graz, Austria.
authors.forename: Andreas
authors.initials: A
authors.lastname: Leithner
authors.affiliation: Division of Biomedical Research, Medical University of Graz, Graz, Austria.
authors.forename: Beate
authors.initials: B
authors.lastname: Rinner
mesh_terms: D001343:Autophagy / Q000187:drug effects*; D000071187:Autophagy-Related Protein 5 / Q000378:metabolism; D000071186:Beclin-1 / Q000378:metabolism; D015415:Biomarkers / Q000378:metabolism; D001859:Bone Neoplasms / Q000378:metabolism; D000069286:Bortezomib / Q000494:pharmacology*; D020169:Caspases / Q000378:metabolism*; D045744:Cell Line, Tumor; D002813:Chondrosarcoma / Q000378:metabolism*; D006801:Humans; D008928:Mitochondria / Q000378:metabolism*; D061988:Proteasome Inhibitors / Q000494:pharmacology*; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: D000071187:Autophagy-Related Protein 5; D000071186:Beclin-1; D015415:Biomarkers; D061988:Proteasome Inhibitors; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D000069286:Bortezomib; D020169:Caspases