PKCε Is an Essential Mediator of Prostate Cancer Bone Metastasis.

Authors

Alvaro Gutierrez-Uzquiza, University of Pennsylvania
Cynthia Lopez-Haber University of Pennsylvania
Danielle L. Jernigan, Drexel University
Alessandro Fatatis, Thomas Jefferson UniversityFollow
Marcelo G. Kazanietz, University of Pennsylvania

Document Type

Article

Presentation Date

9-1-2015

Comments

This article has been peer reviewed. It is the authors' final version prior to publication in Molecular Cancer Research

Volume 13, Issue 9, September 2015, Pages 1336-1346

The published version is available at DOI: 10.1158/1541-7786.MCR-15-0111. Copyright © American Association for Cancer Research

Abstract

UNLABELLED: 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.

IMPLICATIONS: 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.

Recommended Citation

Gutierrez-Uzquiza, Alvaro; Lopez-Haber, Cynthia University of Pennsylvania; Jernigan, Danielle L.; Fatatis, Alessandro; and Kazanietz, Marcelo G., "PKCε Is an Essential Mediator of Prostate Cancer Bone Metastasis." (2015). Kimmel Cancer Center Papers, Presentations, and Grand Rounds. Paper 38.
https://jdc.jefferson.edu/kimmelgrandrounds/38