Chromosome translocation may lead to PRK1-dependent anticancer drug resistance in yeast via endocytic actin network deregulation.
Chromosome translocations are often observed in cancer cells, being in some cases the cause of neoplastic transformation while in others the results of it. In previous works, we reproduced this major genomic rearrangement by bridge-induced chromosome translocation (BIT) technology in the model eukaryote Saccharomyces cerevisiae and reported that it affects DNA replication, cell cycle, karyogamy, and cytokinesis while it produces genetic instability. In the present work, we further discovered that this event can lead to increased resistance to anticancer chemicals like Doxorubicin and Latrunculin A via an endocytic actin network deregulation triggered by over-expression of the PRK1 serine/threonine protein kinase gene. This effect is further enhanced by the overexpression of PDR1 and PDR3 transcriptional regulators of pleiotropic drug resistance factors. However, when the actin depolymerizing drug Latrunculin A is forcefully allowed to penetrate through their altered cell wall and membrane barriers, it can kill translocants more efficiently than wild type cells. These observations provide an example of an acquired anticancer drug resistance mechanism and could serve as a lead to how it might be overcome, as any treatment inhibiting genome rearrangements could increase the positive outcome of anticancer therapy by lowering cellular drug resistance.
Yeast Molecular Genetics Group, ICGEB, Area Science Park, Padriciano 99, I-34149 Trieste, Italy; Institute of Biochemistry and Physiology of Microorganisms RAS, av. Nauki, 5, Pushchino, Russian Federation.
Dmitri V
DV
Nikitin
Yeast Molecular Genetics Group, ICGEB, Area Science Park, Padriciano 99, I-34149 Trieste, Italy.
Carlo V
CV
Bruschi
Yeast Molecular Genetics Group, ICGEB, Area Science Park, Padriciano 99, I-34149 Trieste, Italy.
Jason
J
Sims
Genetics Division, Department of Cell Biology, University of Salzburg, Hellbrunnerstrasse 34, A-5020 Salzburg, Austria.
Michael
M
Breitenbach
Genetics Division, Department of Cell Biology, University of Salzburg, Hellbrunnerstrasse 34, A-5020 Salzburg, Austria.
Mark
M
Rinnerthaler
Yeast Molecular Genetics Group, ICGEB, Area Science Park, Padriciano 99, I-34149 Trieste, Italy. Electronic address: tosato@icgeb.org.
Valentina
V
Tosato
D000199:Actins / Q000235:genetics* / Q000378:metabolism / Q000648:ultrastructure; D000970:Antineoplastic Agents / Q000494:pharmacology*; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology; D015825:Chromosomes, Fungal / Q000235:genetics*; D004317:Doxorubicin / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D012441:Saccharomyces cerevisiae / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D029701:Saccharomyces cerevisiae Proteins / Q000378:metabolism*; D053778:Thiazolidines / Q000494:pharmacology; D014178:Translocation, Genetic
D000199:Actins; D000970:Antineoplastic Agents; D019086:Bridged Bicyclo Compounds, Heterocyclic; D029701:Saccharomyces cerevisiae Proteins; D053778:Thiazolidines; D004317:Doxorubicin; C094326:PRK1 protein, S cerevisiae; D017346:Protein Serine-Threonine Kinases; C037067:latrunculin A
BIT; Doxorubicin; Genome rearrangements; Multidrug pumps; Saccharomyces cerevisiae