Genomic Analysis of Taxol Resistance---TXR Genes and Signaling Pathways

  • Chao, Chuck C.-K. (PI)

Project: National Science and Technology CouncilNational Science and Technology Council Academic Grants

Project Details

Abstract

Taxol cause mitotic damage, and is widely used in anticancer therapy because of its great potency. However, the effective use of taxol is limited by the development of drug resistance in cancer cells. Although biochemical and pharmacological studies have implied underlying mechanisms for the resistance, the specific genes responsible for the resistance are not well revealed. Intending to search in a genomewide scale for candidate genes that may participate in chemoresistance, we have initially identified a few taxol resistance (txr) genes and started to characterize their role in chemoresistance by cell growth inhibition (MTT) assay. Among these txr genes, ABC transporters (ABCB1 and ABCG2) are prominently overexpressed in acquired taxol resistant ovarian cancer cell model. FKBP5 and androgen receptor (AR) genes are also overexpressed and functionally annotated as txr genes in these resistance cells. Notably, FKBP5 and AR genes are muturally regulated, and above mentioned txr genes appear to be coordinately regulated by FKBP5/AR because artificially change their expression significantly altered the txr transcript levels. In addition, FKBP5 co-immunoprecipitated with AR, and vice versa. These preliminary results together with literature search strongly suggest the importance of these txr genes in taxol resistance. Thus, the important findings prompt us to pursue the mechanism underlying the regulation and action of these txr genes in taxol resistance. We hypothesize that FKBP5 assists nuclear tranlocation of AR to upregulate txr genes expression and responsible for taxol resistance phenotype. The specific aims for a three-year proposal include: 1) Characterization of top-ranked three txr genes in taxol resistance using ovarian carcinoma cell and mouse tumor xenograft models. 2) Regulation of these txr genes by AR/FKBP5. 3) Finding the best drug target singularly or in combination in cell and mouse models. Accomplishment of these novel works will likely shed light on the basic understanding of taxol resistance, and provide important information for development of novel regimen of taxol-based chemotherapy in cancer treatment.

Project IDs

Project ID:PC10308-0905
External Project ID:MOST103-2320-B182-031
StatusFinished
Effective start/end date01/08/1431/07/15

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