Increased sensitivity to platinating agents and arsenite in human ovarian cancer by downregulation of ASNA1.
Platinating agents constitute the first line treatment for ovarian cancer but treatment failure is common because of intrinsic and acquired resistance. Cancer cells develop the RASP-phenotype (cross resistance against arsenite, antimonite and platinum) associated with decreased accumulation of cisplatin and arsenite. ASNA1 is a possible subunit of a transport system for cisplatin and arsenite due to homology to arsA, an ATPase in the E. coli ars-complex responsible for efflux of arsenite and antimonite. Eukaryotic ASNA1 is a targeting factor for membrane insertion of tail-anchored proteins involved in the secretory pathway and cellular stress responses. The purpose with this study was to evaluate if ASNA1 expression influenced cisplatin, carboplatin, oxaliplatin or arsenite sensitivity in ovarian cancer. Human ovarian cancer cell line 2008 was transfected with a sense or an antisense ASNA1 construct. ASNA1 downregulated and overexpressing clones were identified by Western blots. Cell growth and chemosensitivity was determined by the MTT assay. Down-regulated ASNA1 expression was associated with retarded growth and increased sensitivity to cisplatin, carboplatin, oxaliplatin and arsenite whereas the cisplatin resistant 2008/A overexpresses ASNA1. These observations support the hypothesis that ASNA1 is a target to overcome platinum resistance in ovarian cancer.
Hemmingsson
Oskar
O
Department of Surgical and Perioperative Sciences, Surgery, Umeå University, S-90185 Umeå, Sweden. oskar.hemmingsson@surgery.umu.se
Nöjd
Mikael
M
Kao
Gautam
G
Naredi
Peter
P
D000970:Antineoplastic Agents / Q000494:pharmacology*; D053501:Arsenite Transporting ATPases / Q000096:biosynthesis / Q000187:drug effects* / Q000235:genetics; D018053:Arsenites / Q000494:pharmacology*; D015153:Blotting, Western; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D015536:Down-Regulation; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005260:Female; D006801:Humans; D010051:Ovarian Neoplasms / Q000235:genetics*; D017671:Platinum Compounds / Q000494:pharmacology*; D014162:Transfection
D000970:Antineoplastic Agents; D018053:Arsenites; C489667:GET3 protein, human; D017671:Platinum Compounds; D053501:Arsenite Transporting ATPases; C015001:arsenite