Mitosis Phase Enrichment with Identification of Mitotic Centromere-Associated Kinesin As a Therapeutic Target in Castration-Resistant Prostate Cancer

Kanishka Sircar,Eleni Efstathiou,Patricia Troncoso,Limei Hu,Heng Huang,Nora Navone,David Cogdell,Armen Aprikian,Wei Zhang,Jasreman Dhillon,Yuexin Liu,Irina Agoulnik

doi:10.1371/journal.pone.0031259

Abstract

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.

Highlights

Prostate cancer is the second leading cause of cancer-specific mortality in the United States [1], with most deaths occurring after failure of androgen-deprivation therapy when the tumor grows as castration-resistant prostate cancer (CRPC), killing the patient within a median period of 18 months
To validate the putative transcriptomic switch to a mitosis-phase program in CRPC at the protein level, we used nuclear phosphohistone H3 immunostaining as a mitosis-phase marker, as histones are phosphorylated at the end of prophase and their phosphorylation peaks at metaphase [7]
Given the vastly different transcriptional profiles and far more aggressive clinical behavior of high Gleason–grade (Gleason grades 4/5) prostate cancer compared with low Gleason–grade (Gleason grade 3) prostate cancer, our data underscores the distinctiveness of CRPC from all histological subtypes of hormone-sensitive prostate cancer (HSPC)

Summary

Introduction

Prostate cancer is the second leading cause of cancer-specific mortality in the United States [1], with most deaths occurring after failure of androgen-deprivation therapy when the tumor grows as castration-resistant prostate cancer (CRPC), killing the patient within a median period of 18 months. An important recent advance in this field was the demonstration that the androgen receptor activates a distinct mitosis-phase transcriptional program in CRPC but not in hormone-sensitive prostate cancer (HSPC) [6], partially explaining the relative success of docetaxel, an anti-mitotic chemotherapeutic agent used to treat CRPC. Those results suggest that other mitosis-phase proteins may be potential targets for therapies treating this stage of disease. We sought to first validate the upregulation of the mitosis-phase transcriptional program at the protein level in CRPC using clinical

Methods

Results

Conclusion