Protein Kinase C-ε Promotes EMT in Breast Cancer

Jain, Kirti; Basu, Alakananda

doi:10.4137/bcbcr.s13640

Cited by 20 publications

(34 citation statements)

References 42 publications

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“…PKCε has been widely associated with the development of epithelial cancers, and has been originally described as an oncogenic kinase that is able to transform fibroblasts through the activation of the Ras-Raf1 signaling pathway and autocrine secretion of TGF-β (19, 36, 37). Numerous laboratories underscored important roles for PKCε in cell cycle progression and the control of cell survival mechanisms (2, 5, 6).…”

Section: Discussionmentioning

confidence: 99%

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PKCϵ Is an Essential Mediator of Prostate Cancer Bone Metastasis

Gutiérrez-Uzquiza

López‐Haber

Jernigan

et al. 2015

Molecular Cancer Research

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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.

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Section: Discussionmentioning

confidence: 99%

“…Moreover, PKCε is required for motility and invasion in various cancer cellular models in culture as well as for metastatic dissemination in vivo . Most remarkably, studies using transgenic PKCε mice established this kinase as a driver of metastatic skin squamous cell carcinoma (15-19). …”

Section: Introductionmentioning

confidence: 99%

PKCϵ Is an Essential Mediator of Prostate Cancer Bone Metastasis

Gutiérrez-Uzquiza

López‐Haber

Jernigan

et al. 2015

Molecular Cancer Research

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“…regulates the epithelial-mesenchymal transition (EMT) and its reverse process, the mesenchyme to epithelial transition (MET) (18,19). We found levels of CTNND1 S268 phosphorylation and PKCe (18,19) activity were inversely correlated with metastatic potential, in that highly metastatic astrocytoma cell lines contained less PKCe and less CTNND1 P-S268 (Fig.…”

Section: Resultsmentioning

confidence: 79%

“…We found levels of CTNND1 S268 phosphorylation and PKCe (18,19) activity were inversely correlated with metastatic potential, in that highly metastatic astrocytoma cell lines contained less PKCe and less CTNND1 P-S268 (Fig. 4A).…”

Section: Resultsmentioning

confidence: 94%

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Catenin delta-1 (CTNND1) phosphorylation controls the mesenchymal to epithelial transition in astrocytic tumors

et al. 2016

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Inactivating mutations of the TSC1/TSC2 complex (TSC1/2) cause tuberous sclerosis (TSC), a hereditary syndrome with neurological symptoms and benign hamartoma tumours in the brain. Since TSC effectors are largely unknown in the human brain, TSC patient cortical tubers were used to uncover hyperphosphorylation unique to TSC primary astrocytes, the cell type affected in the brain. We found abnormal hyperphosphorylation of catenin delta-1 S268, which was reversible by mTOR- specific inhibitors. In contrast, in three metastatic astrocytoma cell lines, S268 was under phosphorylated, suggesting S268 phosphorylation controls metastasis. TSC astrocytes appeared epithelial (i.e. tightly adherent, less motile, and epithelial (E)-cadherin positive), whereas wild-type astrocytes were mesenchymal (i.e. E-cadherin negative and highly motile). Despite their epithelial phenotype, TSC astrocytes outgrew contact inhibition, and monolayers sporadically generated tuberous foci, a phenotype blocked by the mTOR inhibitor, Torin1. Also, mTOR-regulated phosphokinase C epsilon (PKCe) activity induced phosphorylation of catenin delta-1 S268, which in turn mediated cell-cell adhesion in astrocytes. The mTOR-dependent, epithelial phenotype of TSC astrocytes suggests TSC1/2 and mTOR tune the phosphorylation level of catenin delta-1 by controlling PKCe activity, thereby regulating the mesenchymal-epithelial-transition (MET). Thus, some forms of TSC could be treated with PKCe inhibitors, while metastasis of astrocytomas might be blocked by PKCe stimulators.

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Polyphenols fromArtemisia annuaL Inhibit Adhesion and EMT of Highly Metastatic Breast Cancer Cells MDA-MB-231

Lee

Panchanathan

et al. 2016

Phytother. Res.

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Recent evidence suggests that polyphenolic compounds from plants have anti-invasion and anti-metastasis capabilities. The Korean annual weed, Artemisia annua L., has been used as a folk medicine for treatment of various diseases. Here, we isolated and characterized polyphenols from Korean A. annua L (pKAL). We investigated anti-metastatic effects of pKAL on the highly metastatic MDA-MB-231 breast cancer cells especially focusing on cancer cell adhesion to the endothelial cell and epithelial-mesenchymal transition (EMT). Firstly, pKAL inhibited cell viability of MDA-MB-231 cells in a dose-dependent manner, but not that of human umbilical vein endothelial cells (ECs). Polyphenols from Korean A. annua L inhibited the adhesion of MDA-MB-231 cells to ECs through reducing vascular cell adhesion molecule-1 expression of MDA-MB-231 and ECs, but not intracellular adhesion molecule-1 at the concentrations where pKAL did not influence the cell viability of either MDA-MB-231 cells nor EC. Further, pKAL inhibited tumor necrosis factor-activated MDA-MB-231 breast cancer cell invasion through inhibition of matrix metalloproteinase-2 and matrix metalloproteinase-9 and EMT. Moreover, pKAL inhibited phosphorylation of Akt, but not that of protein kinase C. These results suggest that pKAL may serve as a therapeutic agent against cancer metastasis at least in part by inhibiting the cancer cell adhesion to ECs through suppression of vascular cell adhesion molecule-1 and invasion through suppression of EMT. Copyright © 2016 John Wiley & Sons, Ltd.

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Protein Kinase C-ε Promotes EMT in Breast Cancer

Cited by 20 publications

References 42 publications

PKCϵ Is an Essential Mediator of Prostate Cancer Bone Metastasis

PKCϵ Is an Essential Mediator of Prostate Cancer Bone Metastasis

Catenin delta-1 (CTNND1) phosphorylation controls the mesenchymal to epithelial transition in astrocytic tumors

Polyphenols fromArtemisia annuaL Inhibit Adhesion and EMT of Highly Metastatic Breast Cancer Cells MDA-MB-231

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