title: PKCε Is an Essential Mediator of Prostate Cancer Bone Metastasis.
abstract: The bone is a preferred site for metastatic homing of prostate cancer cells. Once prostate cancer patients develop skeletal metastases, they eventually succumb to the disease; therefore, it is imperative to identify key molecular drivers of this process. This study examines the involvement of protein kinase C epsilon (PKCε), an oncogenic protein that is abnormally overexpressed in human tumor specimens and cell lines, on prostate cancer cell bone metastasis. PC3-ML cells, a highly invasive prostate cancer PC3 derivative with bone metastatic colonization properties, failed to induce skeletal metastatic foci upon inoculation into nude mice when PKCε expression was silenced using shRNA. Interestingly, while PKCε depletion had only marginal effects on the proliferative, adhesive, and migratory capacities of PC3-ML cells in vitro or in the growth of xenografts upon s.c. inoculation, it caused a significant reduction in cell invasiveness. Notably, PKCε was required for transendothelial cell migration (TEM) as well as for the growth of PC3-ML cells in a bone biomimetic environment. At a mechanistic level, PKCε depletion abrogates the expression of IL1β, a cytokine implicated in skeletal metastasis. Taken together, PKCε is a key factor for driving the formation of bone metastasis by prostate cancer cells and is a potential therapeutic target for advanced stages of the disease.
  
  
  CONCLUSIONS
  This study uncovers an important new function of PKCε in the dissemination of cancer cells to the bone; thus, highlighting the promising potential of this oncogenic kinase as a therapeutic target for skeletal metastasis.
authors.affiliation: Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Alvaro
authors.initials: A
authors.lastname: Gutierrez-Uzquiza
authors.affiliation: Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Cynthia
authors.initials: C
authors.lastname: Lopez-Haber
authors.affiliation: Department of Pharmacology and Physiology, Drexel University College of Medicine, Philadelphia, Pennsylvania.
authors.forename: Danielle L
authors.initials: DL
authors.lastname: Jernigan
authors.affiliation: Department of Pharmacology and Physiology, Drexel University College of Medicine, Philadelphia, Pennsylvania. Program in Biology of Prostate Cancer, Sidney Kimmel Cancer Center, Philadelphia, Pennsylvania.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Fatatis
authors.affiliation: Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania. marcelog@upenn.edu.
authors.forename: Marcelo G
authors.initials: MG
authors.lastname: Kazanietz
mesh_terms: D000818:Animals; D001859:Bone Neoplasms / Q000556:secondary*; D002448:Cell Adhesion; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D064593:Heterografts; D006801:Humans; D053583:Interleukin-1beta / Q000378:metabolism; D008297:Male; D056892:Mediator Complex; D051379:Mice; D008819:Mice, Nude; D011471:Prostatic Neoplasms / Q000378:metabolism* / Q000473:pathology*; D051744:Protein Kinase C-epsilon / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000378:metabolism
chemical_list: D053583:Interleukin-1beta; D056892:Mediator Complex; D034741:RNA, Small Interfering; D051744:Protein Kinase C-epsilon