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(Reference retrieved automatically from Web of Science through information on FAPESP grant and its corresponding number as mentioned in the publication by the authors.)

Chemogenomic study of gemcitabine using Saccharomyces cerevisiae as model cell-molecular insights about chemoresistance

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Author(s):
Cavalcante, Lucas de Sousa [1] ; Costa-Silva, Tales A. [1] ; Souza, Tiago Antonio [2] ; Ienne, Susan [2] ; Monteiro, Gisele [1]
Total Authors: 5
Affiliation:
[1] Univ Sao Paulo, Fac Ciencias Farmaceut, Dept Tecnol Bioquim Farmaceut, Av Prof Lineu Prestes, 580, B16, Cidade Univ, Sao Paulo 05508000, SP - Brazil
[2] Univ Sao Paulo, GENIAL Genome Invest & Anal Lab, Inst Ciencias Biomed, CEFAP Ctr Facilidades Apoio Pesquisa, Sao Paulo - Brazil
Total Affiliations: 2
Document type: Journal article
Source: Brazilian Journal of Microbiology; v. 51, n. 2, p. 489-496, JUN 2020.
Web of Science Citations: 0
Abstract

Gemcitabine (GEM) is the drug used as first line to treat pancreatic cancer, one of the most devastating human tumors. This peculiar type of tumor develops resistance to several drugs, including GEM, due to its desmoplastic reaction and other features. The GEM chemoresistance has been investigated at molecular level aiming to find a pathway whose inhibition or activation should overcome it. Through next-generation sequencing was performed a chemogenomic assay of GEM using Saccharomyces cerevisiae as model cell and the results showed that more than 40% of genes related to GEM response in yeast possess unknown or dubious function. We choose two yeast mutants to individually validate the fitness defect results observed by chemogenomic assay, Delta hmt1 and Delta csi1, and it was found that in addition to some already described pathways involved in GEM resistance, cells deficient in deneddylation enzyme Cop9 Signalosome Interactor 1 (Csi1p) presented a high sensitivity to GEM. This was confirmed by individual growth analyses of Delta csi1 cells exposed to GEM, and this phenotype was reverted with CSI1 complementation gene. Csi1p is a well-characterized homolog equivalent to human Csn6 subunit of COP9 signalosome (CSN) involved in deneddylation process. We highlighted too that epigenetic alterations, such as methylation mediated by protein arginine methyltransferase 1, play an important role in regulating gemcitabine treatment resistance. Our results point out new unexplored molecular pathways that can be used to overcome GEM resistance: the inhibition of CSN and the arginine methyltransferase activities. (AU)

FAPESP's process: 11/04938-8 - Identification of molecular targets associated to gemcitabine and rebeccamycin analogues resistance using Saccharomyces cerevisiae as model cell
Grantee:Lucas de Sousa Cavalcante
Support Opportunities: Scholarships in Brazil - Master
FAPESP's process: 18/15104-0 - Preclinical assays of glycoprotein asparaginase proteoforms or resistant to serum proteases.
Grantee:Gisele Monteiro
Support Opportunities: Regular Research Grants
FAPESP's process: 09/01303-1 - Characterization of unknown function ORFs involved in Saccharomyces cerevisiae antioxidant response
Grantee:Gisele Monteiro
Support Opportunities: Research Grants - Young Investigators Grants
FAPESP's process: 15/07749-2 - Protein engineering and comparison of microbial expression systems of the biopharmaceutical L-asparaginase
Grantee:Gisele Monteiro
Support Opportunities: Regular Research Grants