umu.sePublications
Change search
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf
ASNA-1 activity modulates sensitivity to cisplatin
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.
2010 (English)In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 70, no 24, 10321-10328 p.Article in journal (Refereed) Published
Abstract [en]

Cancer can be cured by platinum based chemotherapy but resistance is a major cause of treatment failure. Here we present the nematode Caenorhabditis elegans as a model to study interactions between the platinum drug cisplatin and signaling pathways in vivo. Null mutations in a single gene, asna-1, makes worms hypersensitive to cisplatin. The metalloregulated ATPase ASNA-1 promotes insulin secretion and membrane insertion of tail-anchored proteins. Using structural data from ASNA-1 homologs, we identify specific ASNA-1 mutants that are sensitive to cisplatin while still able to promote insulin signaling. Mutational analysis reveals that hypersensitivity of ASNA-1 mutants to cisplatin remains in absence of CEP-1/p53 or apoptosis. Human ASNA1 can substitute for the worm gene, indicating a conserved function. Cisplatin sensitivity is not affected by decreased insulin signaling in wild type nematodes or restored insulin signaling in asna-1 mutants. These findings provide a functional insight into ASNA-1, demonstrate that C. elegans can be used to characterize cisplatin resistance mechanisms and propose that rationally designed drugs against ASNA-1 can sensitize cancer cells to cisplatin.

Place, publisher, year, edition, pages
American Association for Cancer Research , 2010. Vol. 70, no 24, 10321-10328 p.
Keyword [en]
ASNA1, cisplatin, C. elegans, Drug resistance, arsenite
National Category
Cancer and Oncology Pharmaceutical Sciences Cell Biology
Research subject
Surgery; Oncology
Identifiers
URN: urn:nbn:se:umu:diva-37629DOI: 10.1158/0008-5472.CAN-10-1548ISI: 000285334200033PubMedID: 20966125OAI: oai:DiVA.org:umu-37629DiVA: diva2:369453
Available from: 2010-11-10 Created: 2010-11-10 Last updated: 2017-12-12Bibliographically 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

Open Access in DiVA

No full text

Other links

Publisher's full textPubMed

Authority records BETA

Hemmingsson, OskarKao, GautamNaredi, Peter

Search in DiVA

By author/editor
Hemmingsson, OskarKao, GautamStill, MariaNaredi, Peter
By organisation
Surgery
In the same journal
Cancer Research
Cancer and OncologyPharmaceutical SciencesCell Biology

Search outside of DiVA

GoogleGoogle Scholar

doi
pubmed
urn-nbn

Altmetric score

doi
pubmed
urn-nbn
Total: 139 hits
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf