title: Identification of survival-promoting OSIP108 peptide variants and their internalization in human cells.
abstract: The plant-derived decapeptide OSIP108 increases tolerance of yeast and human cells to apoptosis-inducing agents, such as copper and cisplatin. We performed a whole amino acid scan of OSIP108 and conducted structure-activity relationship studies on the induction of cisplatin tolerance (CT) in yeast. The use of cisplatin as apoptosis-inducing trigger in this study should be considered as a tool to better understand the survival-promoting nature of OSIP108 and not for purposes related to anti-cancer treatment. We found that charged residues (Arg, His, Lys, Glu or Asp) or a Pro on positions 4-7 improved OSIP108 activity by 10% or more. The variant OSIP108[G7P] induced the most pronounced tolerance to toxic concentrations of copper and cisplatin in yeast and/or HepG2 cells. Both OSIP108 and OSIP108[G7P] were shown to internalize equally into HeLa cells, but at a higher rate than the inactive OSIP108[E10A], suggesting that the peptides can internalize into cells and that OSIP108 activity is dependent on subsequent intracellular interactions. In conclusion, our studies demonstrated that tolerance/survival-promoting properties of OSIP108 can be significantly improved by single amino acid substitutions, and that these properties are dependent on (an) intracellular target(s), yet to be determined.
authors: Centre of Microbial and Plant Genetics, CMPG, KU Leuven, Kasteelpark Arenberg 20, box 2460, 3001 Leuven, Belgium.
authors: Sara
authors: S
authors: Verbandt
authors: Institute for Molecular Bioscience, University of Queensland, Brisbane, QLD 4072, Australia.
authors: Sónia Troeira
authors: ST
authors: Henriques
authors: Centre of Microbial and Plant Genetics, CMPG, KU Leuven, Kasteelpark Arenberg 20, box 2460, 3001 Leuven, Belgium; Department of Laboratory Medicine, University Hospital Gasthuisberg, Herestraat 49, 3000 Leuven, Belgium.
authors: Pieter
authors: P
authors: Spincemaille
authors: Institute for Molecular Bioscience, University of Queensland, Brisbane, QLD 4072, Australia.
authors: Peta J
authors: PJ
authors: Harvey
authors: Clinic for Transplantation Medicine, Münster University Hospital, Albert-Schweitzer-Campus 1, Building A14, D-48149 Münster, Germany.
authors: Gursimran
authors: G
authors: Chandhok
authors: Clinic for Transplantation Medicine, Münster University Hospital, Albert-Schweitzer-Campus 1, Building A14, D-48149 Münster, Germany.
authors: Vanessa
authors: V
authors: Sauer
authors: Centre of Microbial and Plant Genetics, CMPG, KU Leuven, Kasteelpark Arenberg 20, box 2460, 3001 Leuven, Belgium; Department of Plant Systems Biology, VIB, Technologiepark 927, 9052 Ghent, Belgium.
authors: Barbara
authors: B
authors: De Coninck
authors: Department of Hepatology and Metabolic Center, University Hospital Gasthuisberg, Herestraat 49, 3000 Leuven, Belgium.
authors: David
authors: D
authors: Cassiman
authors: Institute for Molecular Bioscience, University of Queensland, Brisbane, QLD 4072, Australia.
authors: David J
authors: DJ
authors: Craik
authors: Centre of Microbial and Plant Genetics, CMPG, KU Leuven, Kasteelpark Arenberg 20, box 2460, 3001 Leuven, Belgium; Department of Plant Systems Biology, VIB, Technologiepark 927, 9052 Ghent, Belgium. Electronic address: bruno.cammue@biw.kuleuven.be.
authors: Bruno P A
authors: BPA
authors: Cammue
authors: Centre of Microbial and Plant Genetics, CMPG, KU Leuven, Kasteelpark Arenberg 20, box 2460, 3001 Leuven, Belgium; Department of Plant Systems Biology, VIB, Technologiepark 927, 9052 Ghent, Belgium.
authors: Kaat
authors: K
authors: De Cremer
authors: Centre of Microbial and Plant Genetics, CMPG, KU Leuven, Kasteelpark Arenberg 20, box 2460, 3001 Leuven, Belgium.
authors: Karin
authors: K
authors: Thevissen
mesh_terms: D029681:Arabidopsis Proteins / Q000235:genetics* / Q000493:pharmacokinetics* / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects; D002945:Cisplatin / Q000493:pharmacokinetics / Q000494:pharmacology; D025141:Drug Resistance, Fungal / Q000187:drug effects; D006367:HeLa Cells; D056945:Hep G2 Cells; D006801:Humans; D012441:Saccharomyces cerevisiae / Q000378:metabolism
chemical_list: D029681:Arabidopsis Proteins; C000594979:methionyl-leucyl-cysteinyl-valyl-leucyl-glutaminyl-glycyl-leucyl-arginyl-glutamic acid; D002945:Cisplatin
keywords: Apoptosis-inducers; Cellular internalization; OSIP108; Structure activity relationship study; Survival