Atypical protein kinase C‐ζ modulates clonogenicity, motility, and secretion of proteolytic enzymes in murine mammary cells

Urtreger, Alejandro J.; Grossoni, Valeria C.; Falbo, Karina B.; Kazanietz, Marcelo G.; Joffé, Elisa D. Bal de Kier

doi:10.1002/mc.20066

Cited by 35 publications

(30 citation statements)

References 53 publications

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“…Furthermore, the expression of proteases has been associated with poor prognosis of breast cancer patients [51,52]. It has been reported in various cellular models that overexpression of different PKCs augments the secretion of both uPA and MMPs [36,53,54]. However, our studies show that overexpression of the classical PKCb1 reduces the secretion of uPA and MMP-2 in LM3 mammary tumor cells.…”

Section: Discussioncontrasting

confidence: 53%

“…Forty-eight hours after transfection, cells were selected using 500 lg/ml G418. After selection, resistant clones were pooled to avoid clonal variations [36].…”

Section: Cell Line and Culture Conditionsmentioning

confidence: 99%

“…Clonal cell growth was studied as previously described [36]. Briefly, single-cell suspensions containing 500-1,000 cells were seeded onto 60 mm plastic dishes in MEM with 10% FCS.…”

Section: Clonogenic Assaymentioning

confidence: 99%

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Opposite effects of protein kinase C beta1 (PKCβ1) and PKCε in the metastatic potential of a breast cancer murine model

Grossoni

Todaro

Kazanietz

et al. 2009

Breast Cancer Res Treat

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In this paper we investigated whether protein kinase C (PKC) beta1 and PKCepsilon, members of the classical and novel PKC family, respectively, induce phenotypic alterations that could be associated with tumor progression and metastatic dissemination in a murine model of breast cancer. Stable overexpression of PKCbeta1 in LM3 cells altered their ability to proliferate, adhere, and survive, and impaired their tumorigenicity and metastatic capacity. Moreover, PKCbeta1 induced the re-expression of fibronectin, an extracellular matrix glycoprotein which loss has been associated with the acquisition of a transformed phenotype in different cell models, and exerted an important inhibition on proteases production, effects that probably impact on LM3 invasiveness and dissemination. Conversely, PKCepsilon overexpression enhanced LM3 survival, anchorage-independent growth, and caused a significant increase in spontaneous lung metastasis. Our results suggest PKCbeta1 functions as an inhibitory protein for tumor growth and metastasis dissemination whereas PKCepsilon drives metastatic dissemination without affecting primary tumor growth.

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Section: Discussioncontrasting

confidence: 53%

“…Forty-eight hours after transfection, cells were selected using 500 lg/ml G418. After selection, resistant clones were pooled to avoid clonal variations [36].…”

Section: Cell Line and Culture Conditionsmentioning

confidence: 99%

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Opposite effects of protein kinase C beta1 (PKCβ1) and PKCε in the metastatic potential of a breast cancer murine model

Grossoni

Todaro

Kazanietz

et al. 2009

Breast Cancer Res Treat

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“…We recently showed that the atypical PKC isoform PKCζ is a signaling intermediate for melanocyte dendrite formation [21]. PKCζ regulates mitogenesis, cell polarity and migration in other cell types and a recent study showed that PKCζ activation stimulates filopodia formation in motile cells [22][23][24][25]. Because of the importance of filopodia for melanosome transport and transfer in human melanocytes, PKCζ activation is likely to increase both dendricity and melanosome transfer to keratinocytes [26].…”

Section: Introductionmentioning

confidence: 99%

Prostaglandin E2 regulates melanocyte dendrite formation through activation of PKCζ

Scott

Fricke

Fender

et al. 2007

Experimental Cell Research

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Prostaglandins are lipid signaling intermediates released by keratinocytes in response to ultraviolet irradiation (UVR) in the skin. The main prostaglandin released following UVR is PGE 2 , a ligand for 4 related G-protein coupled receptors (EP 1 , EP 2 , EP 3 and EP 4 ). Our previous work established that PGE 2 stimulates melanocyte dendrite formation through activation of the EP 1 and EP 3 receptors. The purpose of the present report is to define the signaling intermediates involved in EP 1 and EP 3 -dependent dendrite formation in human melanocytes. We recently showed that activation of the atypical PKCζ isoform stimulates melanocyte dendricity in response to treatment with lysophosphatidylcholine. We therefore examined the potential contribution of PKCζ activation on EP 1 and EP 3 -dependent dendrite formation in melanocytes. Stimulation of the EP 1 and EP 3 receptors by selective agonists activated PKCζ, and inhibition of PKCζ activation abrogated EP 1 and EP 3 -receptor mediated melanocyte dendricity. Because of the importance of Rho-GTP binding proteins in the regulation of melanocyte dendricity, we also examined the effect of EP 1 and EP 3 receptor activation on Rac and Rho activity. Neither Rac nor Rho was activated upon treatment with EP 1,3 -receptor agonists. We show that melanocytes express only the EP 3A1 isoform, but not the EP 3B receptor isoform, previously associated with Rho activation, consistent with a lack of Rho stimulation by EP 3 agonists. Our data suggest that PKCζ activation plays a predominant role in regulation of PGE 2 -dependent melanocyte dendricity.

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“…Altered PKC expression is observed in many tumors, and there is a large body of evidence linking PKC to invasion involving MMPs including MMP-9 (21,22). PKC activity, in particular that of nPKC, is of great interest with regard to T cell activation and consequently inflammatory diseases such as asthma, inflammatory bowel disease, and multiple sclerosis (23).…”

mentioning

confidence: 99%

Protein Kinase C Isoforms ζ and ι Mediate Collagenase Expression and Cartilage Destruction via STAT3- and ERK-dependent c-fos Induction

Litherland

Elias

Wang

et al. 2010

Journal of Biological Chemistry

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The protein kinase C (PKC) signaling pathway is a major regulator of cellular functions and is implicated in pathologies involving extracellular matrix remodeling. Inflammatory joint disease is characterized by excessive extracellular matrix catabolism, and here we assess the role of PKC in the induction of the collagenases, matrix metalloproteinase (MMP)-1 and MMP-13, in human chondrocytes by the potent cytokine stimulus interleukin-1 (IL-1) in combination with oncostatin M (OSM). IL-1 ؉ OSM-stimulated collagenolysis and gelatinase activity were ameliorated by pharmacological PKC inhibition in bovine cartilage, as was collagenase gene induction in human chondrocytes. Small interfering RNA-mediated silencing of PKC gene expression showed that both novel (nPKC␦, nPKC) and atypical (aPKC, aPKC) isoforms were involved in collagenase induction by IL-1. However, MMP1 and MMP13 induction by IL-1 ؉ OSM was inhibited only by aPKC silencing, suggesting that only atypical isoforms play a significant role in complex inflammatory milieus. Silencing of either aPKC led to diminished IL-1 ؉ OSM-dependent extracellular signal-regulated kinase (ERK) and signal transducer and activator of transcription (STAT) 3 phosphorylation, and c-fos expression. STAT3 gene silencing or ERK pathway inhibition also resulted in loss of IL-1 ؉ OSM-stimulated c-fos and collagenase expression. Silencing of c-fos and c-jun expression was sufficient to abrogate IL-1 ؉ OSM-stimulated collagenase gene induction, and overexpression of both c-fos and c-jun was sufficient to drive transcription from the MMP1 promoter in the absence of a stimulus. Our data identify atypical PKC isozymes as STAT and ERK activators that mediate c-fos and collagenase expression during IL-1 ؉ OSM synergy in human chondrocytes. aPKCs may constitute potential therapeutic targets for inflammatory joint diseases involving increased collagenase expression.Inflammation is a major characteristic of joint diseases such as rheumatoid arthritis and osteoarthritis (OA), 3 during which inflammatory mediators released by infiltrating immune cells as well as resident joint cells induce alterations in gene expression that can lead to ECM degradation (1, 2). Cytokines such as interleukin (IL-)1, IL-17, and tumor necrosis factor ␣ (TNF␣) are key mediators thought to be involved in promoting inflammatory responses in such destructive joint diseases (3, 4). We have shown that the IL-6 family cytokines oncostatin M (OSM) and IL-6 markedly exacerbate the catabolic potential of these mediators, synergistically promoting cartilage ECM catabolism both in vitro and in vivo (5-9).Chondrocytes are the only resident cell type in normal articular cartilage and function to preserve homeostasis. This is achieved by balancing the expression of ECM components with catabolic factors such as the matrix metalloproteinases (MMPs), which collectively can degrade all the ECM macromolecules. During inflammatory joint diseases, chondrocytes are stimulated to secrete elevated levels of MMPs that, once activated, media...

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Atypical protein kinase C‐ζ modulates clonogenicity, motility, and secretion of proteolytic enzymes in murine mammary cells

Cited by 35 publications

References 53 publications

Opposite effects of protein kinase C beta1 (PKCβ1) and PKCε in the metastatic potential of a breast cancer murine model

Opposite effects of protein kinase C beta1 (PKCβ1) and PKCε in the metastatic potential of a breast cancer murine model

Prostaglandin E2 regulates melanocyte dendrite formation through activation of PKCζ

Protein Kinase C Isoforms ζ and ι Mediate Collagenase Expression and Cartilage Destruction via STAT3- and ERK-dependent c-fos Induction

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