Genome-wide association analysis identified splicing single nucleotide polymorphism in CFLAR predictive of triptolide chemo-sensitivity.

Lata Chauhan,Taraswi Mitra-Ghosh,Jatinder K Lamba,Brooke L Fridley,Tanya Feldberg,Neha Bhise,Gregory D Jenkins

doi:10.1186/s12864-015-1614-1

Abstract

BackgroundTriptolide is a therapeutic diterpenoid derived from the Chinese herb Tripterygium wilfordii Hook f. Triptolide has been shown to induce apoptosis by activation of pro-apoptotic proteins, inhibiting NFkB and c-KIT pathways, suppressing the Jak2 transcription, activating MAPK8/JNK signaling and modulating the heat shock responses.ResultsIn the present study, we used lymphoblast cell lines (LCLs) derived from 55 unrelated Caucasian subjects to identify genetic markers predictive of cellular sensitivity to triptolide using genome wide association study. Our results identified SNPs on chromosome 2 associated with triptolide IC50 (p < 0.0001). This region included biologically interesting genes as CFLAR, PPIl3, Caspase 8/10, NFkB and STAT6. Identification of a splicing-SNP rs10190751, which regulates CFLAR alternatively spliced isoforms predictive of the triptolide cytotoxicity suggests its role in triptolides action. Our results from functional studies in Panc-1 cell lines further demonstrate potential role of CFLAR in triptolide toxicity. Analysis of gene-expression with cytotoxicity identified JAK1 expression to be a significant predictor of triptolide sensitivity.ConclusionsOverall out results identified genetic factors associated with triptolide chemo-sensitivity thereby opening up opportunities to better understand its mechanism of action as well as utilize these biomarkers to predict therapeutic response in patients.Electronic supplementary materialThe online version of this article (doi:10.1186/s12864-015-1614-1) contains supplementary material, which is available to authorized users.

Highlights

Triptolide is a therapeutic diterpenoid derived from the Chinese herb Tripterygium wilfordii Hook f
We evaluated the impact of genetic variations and gene expression profiles predictive of triptolide cytotoxicity using Epstein-Barr-virus transformed lymphoblastoid cell lines (LCLs) that are part of International HapMap project [12]
Genetic associations with triptolide IC50 in LCLs We evaluated 55 LCLs derived from unrelated subjects with Caucasian ancestry for cellular sensitivity to triptolide

Summary

Introduction

Triptolide is a therapeutic diterpenoid derived from the Chinese herb Tripterygium wilfordii Hook f. Triptolide has been shown to induce apoptosis by activation of pro-apoptotic proteins, inhibiting NFkB and c-KIT pathways, suppressing the Jak transcription, activating MAPK8/JNK signaling and modulating the heat shock responses. Triptolide is a biological diterpenoid derived from the Chinese herb Tripterygium wilfordii HOOK f. It has been shown to have influence on several anti-tumor target genes and inhibit tumors by altering multiple signaling pathways, such as, inhibition of NFκB and c-KIT pathway [3], inhibition of Jak transcription [4], inducing apoptotic. We evaluated the impact of genetic variations and gene expression profiles predictive of triptolide cytotoxicity using Epstein-Barr-virus transformed lymphoblastoid cell lines (LCLs) that are part of International HapMap project (www.hapMap.org) [12]. We further validated the functional significance of CFLAR in pancreatic cell lines

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