title: Mitosis phase enrichment with identification of mitotic centromere-associated kinesin as a therapeutic target in castration-resistant prostate cancer.
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.
authors.affiliation: Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America. ksircar@mdanderson.org
authors.forename: Kanishka
authors.initials: K
authors.lastname: Sircar
authors.forename: Heng
authors.initials: H
authors.lastname: Huang
authors.forename: Limei
authors.initials: L
authors.lastname: Hu
authors.forename: Yuexin
authors.initials: Y
authors.lastname: Liu
authors.forename: Jasreman
authors.initials: J
authors.lastname: Dhillon
authors.forename: David
authors.initials: D
authors.lastname: Cogdell
authors.forename: Armen
authors.initials: A
authors.lastname: Aprikian
authors.forename: Eleni
authors.initials: E
authors.lastname: Efstathiou
authors.forename: Nora
authors.initials: N
authors.lastname: Navone
authors.forename: Patricia
authors.initials: P
authors.lastname: Troncoso
authors.forename: Wei
authors.initials: W
authors.lastname: Zhang
mesh_terms: D000728:Androgens / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology; D002369:Castration; D018385:Centrosome / Q000187:drug effects / Q000378:metabolism; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D006801:Humans; D016547:Kinesins / Q000378:metabolism*; D008297:Male; D008938:Mitosis; D058990:Molecular Targeted Therapy; D060787:Neoplasm Grading; D011471:Prostatic Neoplasms / Q000473:pathology* / Q000601:surgery*; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D000728:Androgens; D000970:Antineoplastic Agents; C091489:KIF2C protein, human; D016547:Kinesins