Genetic and cellular sensitivity of Caenorhabditis elegans to the chemotherapeutic agent cisplatin

Disease Models & Mechanisms
Francisco Javier García-RodríguezJulián Cerón

Abstract

Cisplatin and derivatives are commonly used as chemotherapeutic agents. Although the cytotoxic action of cisplatin on cancer cells is very efficient, clinical oncologists need to deal with two major difficulties, namely the onset of resistance to the drug and the cytotoxic effect in patients. Here, we used Caenorhabditis elegans to investigate factors influencing the response to cisplatin in multicellular organisms. In this hermaphroditic model organism, we observed that sperm failure is a major cause of cisplatin-induced infertility. RNA sequencing data indicate that cisplatin triggers a systemic stress response, in which DAF-16/FOXO and SKN-1/NRF2, two conserved transcription factors, are key regulators. We determined that inhibition of the DNA damage-induced apoptotic pathway does not confer cisplatin protection to the animal. However, mutants for the pro-apoptotic BH3-only gene ced-13 are sensitive to cisplatin, suggesting a protective role of the intrinsic apoptotic pathway. Finally, we demonstrated that our system can also be used to identify mutations providing resistance to cisplatin and therefore potential biomarkers of innate cisplatin-refractory patients. We show that mutants for the redox regulator trxr-1, ortholog ...Continue Reading

References

Mar 22, 2001·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·D BarsyteG J Lithgow
Sep 13, 2003·BMC Bioinformatics·Roman L TatusovDarren A Natale
Apr 17, 2004·BMC Developmental Biology·Pavan Kadandale, Andrew Singson
Jun 10, 2004·Methods in Molecular Biology·Anton GartnerAnne M Villeneuve
Oct 19, 2004·Genome Research·Jean-François RualMarc Vidal
Dec 18, 2004·Cell Death and Differentiation·B SchumacherS Shaham
Mar 25, 2005·Nature Reviews. Drug Discovery·Dong Wang, Stephen J Lippard
Feb 24, 2006·Nature Reviews. Molecular Cell Biology·Guillaume Lettre, Michael O Hengartner
May 5, 2006·Nature Reviews. Drug Discovery·Titus Kaletta, Michael O Hengartner
Mar 10, 2007·Cell Death and Differentiation·L StergiouM O Hengartner
Jul 13, 2007·Nature Reviews. Cancer·Lloyd Kelland
Dec 1, 2007·WormBook : the Online Review of C. Elegans Biology·Theresa Stiernagle
Dec 1, 2007·WormBook : the Online Review of C. Elegans Biology·Ronald Ellis, Tim Schedl
Jan 29, 2008·Recent Patents on Anti-cancer Drug Discovery·Markus Galanski
Apr 3, 2008·PloS One·Karin AnestålElias S J Arnér
Oct 15, 2008·Molecular Cancer Therapeutics·Silvia Fernández de MattosEric W-F Lam
Jan 10, 2009·Nature Protocols·Da Wei HuangRichard A Lempicki
Feb 4, 2009·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Jer-Yen Yang, Mien-Chie Hung
Apr 9, 2009·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Jun LuArne Holmgren
Jul 25, 2009·Aging Cell·Sang-Kyu ParkThomas E Johnson
Jul 31, 2009·Oncogene·R Nehme, B Conradt
Aug 12, 2009·Free Radical Biology & Medicine·James W KasparAnil K Jaiswal
Oct 28, 2009·The Journal of Biological Chemistry·Varsha Singh, Alejandro Aballay
Aug 3, 2010·Antioxidants & Redox Signaling·Kelvin YenHeidi A Tissenbaum
Oct 23, 2010·Cancer Research·Oskar HemmingssonPeter Naredi
Jan 5, 2011·Proceedings of the National Academy of Sciences of the United States of America·Jörgen StenvallSimon Tuck
Jun 20, 2012·Journal of Visualized Experiments : JoVE·Montserrat Porta-de-la-RivaJulián Cerón
Feb 23, 2013·Trends in Genetics : TIG·Miriam RodriguezJan E Kammenga
Jul 3, 2013·Nature Methods·Ari E FriedlandJohn A Calarco
Jul 4, 2013·Free Radical Biology & Medicine·Irene Gañán-GómezGuillermo García-Manero
Aug 28, 2013·Genetics·Selma WaaijersMike Boxem
Jan 8, 2014·WormBook : the Online Review of C. Elegans Biology·Coleen T Murphy, Patrick J Hu
Feb 4, 2014·Antioxidants & Redox Signaling·Jun Lu, Arne Holmgren

❮ Previous
Next ❯

Datasets Mentioned

BETA
GSE111654

Methods Mentioned

BETA
RNA-seq
Fluorescence
nuclear translocation
transgenic
PCR

Software Mentioned

ImageJ
Cufflinks
NIS
Elements
TopHat
Cuffdiff
DAVID
SeqSolve NGS
SeqSolve
GraphPad Prism

Related Concepts

Related Feeds

CRISPR (general)

Clustered regularly interspaced short palindromic repeats (CRISPR) are DNA sequences in the genome that are recognized and cleaved by CRISPR-associated proteins (Cas). CRISPR-Cas system enables the editing of genes to create or correct mutations. Discover the latest research on CRISPR here.

CRISPR for Genome Editing

Genome editing technologies enable the editing of genes to create or correct mutations. Clustered regularly interspaced short palindromic repeats (CRISPR) are DNA sequences in the genome that are recognized and cleaved by CRISPR-associated proteins (Cas). Here is the latest research on the use of CRISPR-Cas system in gene editing.

Allergy and Asthma

Allergy and asthma are inflammatory disorders that are triggered by the activation of an allergen-specific regulatory t cell. These t cells become activated when allergens are recognized by allergen-presenting cells. Here is the latest research on allergy and asthma.

CRISPR Ribonucleases Deactivation

CRISPR-Cas system enables the editing of genes to create or correct mutations. This feed focuses on mechanisms that underlie deactivation of CRISPR ribonucleases. Here is the latest research.