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Increased sensitivity to platinating agents and arsenite in human ovarian cancer by downregulation of ASNA1
Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
2009 (English)In: Oncology Reports, ISSN 1021-335X, Vol. 22, no 4, 869-875 p.Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
Spandidos Publications , 2009. Vol. 22, no 4, 869-875 p.
Keyword [en]
ASNA1, cisplatin, carboplatin, oxaliplatin, drug resistance, ovarian cancer
National Category
Pharmaceutical Sciences Cancer and Oncology
Research subject
Surgery; Oncology
URN: urn:nbn:se:umu:diva-33774DOI: 10.3892/or_00000511PubMedID: 19724867OAI: diva2:318032
Available from: 2010-05-06 Created: 2010-05-06 Last updated: 2010-11-19Bibliographically approved
In thesis
1. ASNA1 and cisplatin resistance: studies in C. elegans and in human tumor cells
Open this publication in new window or tab >>ASNA1 and cisplatin resistance: studies in C. elegans and in human tumor cells
2010 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Platinum based chemotherapy is widely used to treat cancer. Cisplatin (diamminedichloroplatinum) combination treatments provide cure for metastatic testicular cancer and prolong survival for patients suffering from ovarian, head and neck, bladder and non small cell lung cancer. Tumors that initially respond to treatment may eventually acquire resistance, resulting in treatment failure. Cisplatin resistant cells are crossresistant to arsenite and antimonite and these metalloids are exported from bacteria by the ars-operon.

In this thesis, we describe the human ArsA homolog, ASNA1, as a protein involved in a novel resistance mechanism to cisplatin, arsenite and antimonite. ASNA1 was downregulated by antisense and siRNA techniques in human melanoma and ovarian carcinoma cell lines. These cells displayed increased sensitivity to arsenite and the platinum based drugs cisplatin, carboplatin and oxaliplatin. In both melanoma and ovarian carcinoma, cisplatin resistant cells overexpressed ASNA1.

Blockage of ASNA1 resulted in increased apoptosis and retarded growth, complicating further characterization of ASNA1 in human cell lines. ASNA1 also promotes insulin signaling and mediates membrane insertion of tail-anchored proteins. To explore different aspects of ASNA1 function with respect to cisplatin resistance, we used the model organism C. elegans.

In the nematode C. elegans, asna-1 (rnai) treated larvae were hypersensitive to cisplatin, arsenite and antimonite. Adult asna-1 mutant worms were cisplatin sensitive and this hypersensitivity was seen even when apoptosis was blocked. Expression of human ASNA1 rescued the cisplatin hypersensitivity in asna-1 mutants, showing conservation of function. Transgene expression of mutated forms of asna-1 separated the cisplatin hypersensitivity phenotype from the insulin signaling phenotype of asna-1 mutants. Three ASNA-1 residues, His164, Cys285 and Cys288 were identified as essential for ASNA-1 promoted cisplatin resistance but not for insulin signaling. Finally, studies of the C. elegans germline revealed increased numbers of apoptotic cells in asna-1 mutants.

In conclusion, C. elegans is a suitable model organism to identify and characterize cisplatin response mechanisms. A targeted therapy against ASNA1 could sensitize cisplatin resistant cells and improve outcome for cancer patients.

Place, publisher, year, edition, pages
Umeå: Umeå Universitet, 2010. 78 p.
Umeå University medical dissertations, ISSN 0346-6612 ; 1390
ASNA1, Cisplatin, C. elegans, Drug resistance, Apoptosis
National Category
Surgery Cancer and Oncology
Research subject
Surgery; Oncology; cellforskning
urn:nbn:se:umu:diva-37661 (URN)978-91-7459-115-6 (ISBN)
Public defence
2010-12-10, Sal B, 9tr, Tandläkarhögskolan, Norrlands Universitetssjukhus, Umeå, 11:17 (Swedish)
Swedish Research Council, K2008-68X-20803-01-3
Available from: 2010-11-19 Created: 2010-11-11 Last updated: 2010-11-19Bibliographically approved

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