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PLoS By Category | Recent
PLoS Articles
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Oncology - Urology
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Mitosis Phase Enrichment with Identification of Mitotic Centromere-Associated Kinesin As a Therapeutic Target in Castration-Resistant Prostate Cancer
Published:
Friday, February 17, 2012
Author:
Kanishka Sircar et al.
by Kanishka Sircar, Heng Huang, Limei Hu, Yuexin Liu, Jasreman Dhillon, David Cogdell, Armen Aprikian, Eleni Efstathiou, Nora Navone, Patricia Troncoso, Wei Zhang
The recently described transcriptomic switch to a mitosis program in castration-resistant prostate cancer (CRPC) suggests that mitotic proteins may be rationally targeted at this lethal stage of the disease. In this study, we showed upregulation of the mitosis-phase at the protein level in our cohort of 51 clinical CRPC cases and found centrosomal aberrations to also occur preferentially in CRPC compared with untreated, high Gleason–grade hormone-sensitive prostate cancer (P<0.0001). Expression profiling of chemotherapy-resistant CRPC samples (n?=?25) was performed, and the results were compared with data from primary chemotherapy-naïve CRPC (n?=?10) and hormone-sensitive prostate cancer cases (n?=?108). Our results showed enrichment of mitosis-phase genes and pathways, with progression to both castration-resistant and chemotherapy-resistant disease. The mitotic centromere-associated kinesin (MCAK) was identified as a novel mitosis-phase target in prostate cancer that was overexpressed in multiple CRPC gene-expression datasets. We found concordant gene expression of MCAK between our parent and murine CRPC xenograft pairs and increased MCAK protein expression with clinical progression of prostate cancer to a castration-resistant disease stage. Knockdown of MCAK arrested the growth of prostate cancer cells suggesting its utility as a potential therapeutic target.
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