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­ASNA-1 influence on apoptosis in C. elegans
Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery. (Surgery)
Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery. (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. (Surgery)
(English)Manuscript (preprint) (Other academic)
Keyword [en]
ASNA1, apoptosis, C. elegans
National Category
Cell and Molecular Biology
Research subject
cellforskning
Identifiers
URN: urn:nbn:se:umu:diva-37646OAI: oai:DiVA.org:umu-37646DiVA: diva2:369550
Available from: 2010-11-11 Created: 2010-11-11 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.
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 1390
Keyword
ASNA1, Cisplatin, C. elegans, Drug resistance, Apoptosis
National Category
Surgery Cancer and Oncology
Research subject
Surgery; Oncology; cellforskning
Identifiers
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)
Opponent
Supervisors
Funder
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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Kao, GautamHemmingsson, OskarNaredi, Peter

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CiteExportLink to record
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