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 IL-1β, 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.

Protein Kinase C Epsilon Cooperates with PTEN Loss for Prostate Tumorigenesis through the CXCL13-CXCR5 Pathway

“…For example, PKCε-depleted lung cancer cells have impaired Rac-dependent cell motility, invasion, and metastatic capacity (Caino et al, 2012b). PKCε promotes the secretion of pro-invasive factors and matrix metalloproteases (MMPs) and has been implicated in the formation of invadopodial-like structures (Gutierrez-Uzquiza et al, 2015; Tachado et al, 2002). One scenario currently under investigation in our laboratory is that Pten loss leads to a hyperactivated PKCε status, as indicated by the enhanced membrane-associated PKCε in Pten-depleted cells (data not shown).…”

Anti-Prostate Cancer Activity of Plant-Derived Bioactive Compounds: a Review

“…EMT is of particular importance in the progression of cancers since epithelial cancer cells that transform to a mesenchymal phenotype tend to be more invasive and thus more prone to metastasis. Furthermore, since metastases that involve the bone drastically reduces the survival rate of patients [1], inhibition of this process presents a potent therapeutic target for impeding the progression of prostate and other cancers.…”

“…Interestingly, vitamin E micelles of berberine exhibited anti-proliferative activity and promoted apoptosis in PC-3 and LNCap cells [32]. Metastasis of prostate cancers is associated with reduced survival rate [1]. Therefore, there is an urgency to identify compounds that inhibit this process.…”

“…Perhaps, most alarming is the observation that prostate cancers have the ability to metastasize to the bone. When this occurs, the 5-year survival rate of patients drops to less than 1% [1]. Despite the overall decreased rate of prostate cancer in the USA, there exists a cancer health disparity where African-American males are twice as likely to be diagnosed with and die from prostate cancer compared to Caucasian men.…”

Protein kinase C in cancer: The top five unanswered questions

“…One scenario that has yet to be surveyed is the potential contribution of PKCε overexpression to a pro-tumorigenic microenvironment. Since early reports linked PKCε oncogenic activity to the release of TGF-β, and later with the production of a number of cytokines and pro-inflammatory factors, 29,32,33 overexpressed PKCε could be envisioned as a major component of autonomous oncogenic autocrine loops or a driver of paracrine interactions with cells from the tumor microenvironment.…”