Mitosis Phase Enrichment with Identification of Mitotic Centromere-Associated Kinesin as a Therapeutic Target in Castration-Resistant Prostate Cancer
Kanishka Sircar, Heng Huang, Limei Hu, Yuexin Liu, Jasreman Dhillon, David Cogdell, Armen Aprikian, Nora Navone, Patricia Troncoso, Wei Zhang. MD Anderson Cancer Center, Houston, TX; UT Arlington, TX; McGill University, Montreal, QC, Canada
Background: Hormone sensitive prostate cancer (HSPC), though initially treatable, eventually progresses to castration resistant prostate cancer (CRPC), which is the lethal phase of this disease. The recently described transcriptomic switch to an androgen receptor mediated mitosis program in CRPC suggests that mitotic proteins may be rationally targeted at this lethal phase of disease progression. We sought to study mitosis phase protein expression in CRPC and identify novel anti-mitotic targets in CRPC using genomic, proteomic and functional approaches.
Design: We examined human CRPC samples (n=51) for expression of the mitosis phase marker p-histone H3 (SC-8656, 1:100) and the centrosomal marker Γ-tubulin (Abcam 27074, 1:400). We performed gene expression profiling (Agilent 44K) of chemotherapy-resistant CRPC samples (n=25) and compared our results with those from publicly available primary chemotherapy-naïve CRPC (n=10) and HSPC (n=149) datasets. Target validation was peformed using immunohistochemistry with functional characterization using si-RNA to our target in LNCaP and C42-B cell lines treated with and without Docetaxel chemotherapy.
Results: Mitosis-phase and centrosomal markers were upregulated at the protein level in CRPC compared with untreated, high Gleason grade hormone-sensitive prostate cancer (P < 0.0001). Gene expression data showed enrichment of mitosis-phase genes and pathways with progression to both castration-resistant and chemotherapy-resistant disease. The mitotic centromere-associated kinesin (MCAK/KIF2C) was identified as a novel mitosis-phase target in prostate cancer that was overexpressed in multiple CRPC gene-expression datasets. KIF2C showed increased protein expression with clinical progression of prostate cancer to CRPC. Si-RNA mediated knockdown of KIF2C arrested the growth of prostate cancer cells and sensitized CRPC cells to Docetaxel chemotherapy.
Conclusions: Mitosis phase is upregulated at the transcript and protein levels with progression to CRPC chemoresistant disease. Mitotic centromere associated kinesin (KIF2C) was identified as a novel therapeutic target in CRPC that may complement standard of care Docetaxel chemotherapy.
Category: Genitourinary (including renal tumors)
Tuesday, March 20, 2012 1:00 PM
Poster Session IV # 112, Tuesday Afternoon