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Establishment of a Clinic-based Biorepository
Published on: May 29, 2017
p63 expression correlates with sensitivity to the Eg5 inhibitor ZD4877 in bladder cancer cells
Lauren Marquis1, Mai Tran, Woonyoung Choi
1Department of Cancer Biology, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Abstract:
Antimitotics such as taxanes are being considered as alternatives to conventional cisplatin-based chemotherapy in patients with bladder cancer, but the molecular determinants of sensitivity or resistance to these agents in bladder cancer cells have not been defined. Here we examined the cytotoxic effects of a novel antimitotic, the Eg5 inhibitor AZD4877, in a molecularly diverse panel of human bladder cancer cell lines. The cells displayed heterogeneous responses to the drug that correlated closely with sensitivity to docetaxel but not with sensitivity to cisplatin. Global gene expression profiling identified p63 as the top gene that was differentially expressed between sensitive and resistant cell lines. Stable knockdown of p63 inhibited cell death induced by either AZD4877 or docetaxel and was associated with decreased proliferation and decreased expression of c-myc. Furthermore, c-myc knockdown also rendered cells resistant to AZD4877 or docetaxel. Together, our results implicate p63 and its downstream target c-myc as determinants of sensitivity to anti-mitotics in bladder cancer cells. Our data also suggest that anti-mitotics and cisplatin target different subsets of bladder cancer cells, a conclusion that may have important implications for the therapy of muscle-invasive bladder cancers.
Insights
Sensitivity to antimitotics like taxanes in bladder cancer cells is linked to p63 and c-myc. These factors, not cisplatin, determine response to novel drugs like AZD4877, impacting treatment strategies.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- Antimitotic agents, including taxanes, are explored as alternatives to cisplatin chemotherapy for bladder cancer.
- Molecular mechanisms underlying sensitivity or resistance to antimitotics in bladder cancer cells remain unclear.
Purpose of the Study:
- To investigate the cytotoxic effects of the novel antimitotic Eg5 inhibitor AZD4877 on diverse human bladder cancer cell lines.
- To identify molecular determinants of sensitivity and resistance to antimitotics in bladder cancer.
Main Methods:
- Testing a panel of human bladder cancer cell lines for sensitivity to AZD4877 and docetaxel.
- Utilizing global gene expression profiling to identify differentially expressed genes between sensitive and resistant cell lines.
- Performing stable knockdown of identified genes (p63, c-myc) to assess their role in drug response.
Main Results:
- Bladder cancer cell lines exhibited heterogeneous responses to AZD4877, correlating with docetaxel sensitivity but not cisplatin sensitivity.
- Gene expression profiling identified p63 as a key differentially expressed gene between sensitive and resistant cell lines.
- p63 knockdown reduced sensitivity to AZD4877 and docetaxel, decreasing proliferation and c-myc expression. c-myc knockdown also conferred resistance to these antimitotics.
Conclusions:
- p63 and its downstream target c-myc are implicated as determinants of sensitivity to antimitotics in bladder cancer.
- Antimitotics and cisplatin appear to target distinct subsets of bladder cancer cells, suggesting potential therapeutic implications for muscle-invasive bladder cancers.
