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
External Project ID:MOST103-2320-B182-031
Status | Finished |
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Effective start/end date | 01/08/14 → 31/07/15 |
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