Protein kinase Cδ signaling downstream of the EGF receptor mediates migration and invasiveness of prostate cancer cells

Kharait, Sourabh; Dhir, Rajiv; Lauffenburger, Douglas A.; Wells, Alan

doi:10.1016/j.bbrc.2006.03.044

Cited by 55 publications

(43 citation statements)

References 31 publications

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“…Our studies therefore support a positive role for PKCδ in the malignant progression of tumors. Actually, elevated expression of PKCδ has been detected in certain tumors Nabha et al, 2005;Villar et al, 2007) and has been found to increase the motility and metastatic potential of tumor cells (Kiley et al, 1999; Alonso-Escolano et al, 2006;Kharait et al, 2006;Villar et al, 2007).The results of this study suggest that PKCδ probably suppresses adherens junctions through interference of homophilic interactions between E-cadherin ectodomains. How does PKCδ exert such a suppressive effect on E-cadherin?…”

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confidence: 52%

Section: Journal Of Cell Sciencementioning

confidence: 99%

“…PKCδ is the most thoroughly studied member of the novel PKC subfamily and is thought to participate in a wide variety of cell functions, including cell proliferation (Ashton et al, 1999;Kitamura et al, 2003), differentiation (Corbit et al, 1999;Pessino et al, 1995), apoptosis (Brodie and Blumberg, 2003;Kajimoto et al, 2004;Zhong et al, 2002) and tumor suppression (Lu et al, 1997;Reddig et al, 1999). Increasing evidence also indicates that PKCδ has a positive role in cell motility (Chen et al, 2007;Gliki et al, 2002;Iwabu et al, 2004;Li et al, 2003) and the metastatic potential of tumor cells (Kiley et al, 1999;Kruger and Reddy, 2003;Alonso-Escolano et al, 2006;Kharait et al, 2006;Villar et al, 2007). However, the role of PKCδ in intercellular junctions remains obscure.…”

Section: +mentioning

confidence: 99%

“…Increasing evidence also indicates that PKCδ has a positive role in cell motility (Chen et al, 2007;Gliki et al, 2002;Iwabu et al, 2004;Li et al, 2003) and the metastatic potential of tumor cells (Kiley et al, 1999;Kruger and Reddy, 2003; Alonso-Escolano et al, 2006;Kharait et al, 2006;Villar et al, 2007). However, the role of PKCδ in intercellular junctions remains obscure.…”

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Functional suppression of E-cadherin by protein kinase Cδ

Chen

2009

Journal of Cell Science

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Journal of Cell Science 514 cell functions, including cell proliferation (Ashton et al., 1999;Kitamura et al., 2003), differentiation (Corbit et al., 1999;Pessino et al., 1995), apoptosis (Brodie and Blumberg, 2003;Kajimoto et al., 2004;Zhong et al., 2002) and tumor suppression (Lu et al., 1997;Reddig et al., 1999). Increasing evidence also indicates that PKCδ has a positive role in cell motility (Chen et al., 2007;Gliki et al., 2002;Iwabu et al., 2004;Li et al., 2003) and the metastatic potential of tumor cells (Kiley et al., 1999;Kruger and Reddy, 2003; Alonso-Escolano et al., 2006;Kharait et al., 2006;Villar et al., 2007). However, the role of PKCδ in intercellular junctions remains obscure. In this study, we aim to explore the role of PKCδ in cellcell junctions using Madin-Darby canine kidney (MDCK) cells as a model. Results Expression of GFP-PKCδ, but not GFP-PKCα, suppresses the homophilic interactions between the ectodomains of E-cadherins in MDCK cellsTo explore the role of PKC in cell-cell junctions, GFP-PKCδ and GFP-PKCα were stably expressed in MDCK cells (Fig. 1A). Expression of either construct in those cells did not alter their growth (data not shown) or their ability to form cell colonies within which the cells are in contact with each other (Fig. 1B). To examine their effect on adherens junctions and tight junctions, cells stably expressing GFP-PKCδ or GFP-PKCα were co-cultured with parental control MDCK cells and then grown to confluence. The cells were fixed and stained for adherens junctions and tight junctions with anti-E-cadherin and anti-ZO-1, respectively. Neither GFP-PKCδ nor GFP-PKCα affected tight junctions of MDCK cells (Fig. 1C,D). However, the fluorescence intensity of E-cadherin at cell-cell contacts in the cells expressing GFP-PKCδ, but not GFP-PKCα, was much weaker than that in adjacent parental MDCK cells (Fig. 1C,D).As the total and cell surface levels of E-cadherins were not altered by GFP-PKCδ (supplementary material Fig. S1), it is unlikely that the decreased fluorescence intensity of E-cadherin was due to suppression of E-cadherin expression. The rat monoclonal anti-Ecadherin (clone ECCD-2) used in Fig. 1C is known to recognize the extracellular domain of E-cadherin, rendering it possible that GFP-PKCδ causes a conformational change on the ectodomain of E-cadherin, which then prevents E-cadherins from detection by the ECCD-2 antibody. To clarify this, a mouse monoclonal antibody (clone 36) that recognizes the cytoplasmic portion of E-cadherins was used. The fluorescence intensity of E-cadherin with the clone 36 antibody did not show differences between control cells and PKCδ-overexpressed cells ( Fig. 2A), supporting the idea that the conformation of E-cadherins rather than their distribution or expression is affected by PKCδ. In addition, we found that the ability of the ECCD-2 antibody, but not the clone 36 antibody, to detect E-cadherin at cell-cell junctions relied on the presence of Ca 2+ in the culture medium, as demonstrated by Ca 2+ -switch assay (Fig. 2B), indicat...

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confidence: 52%

Section: Journal Of Cell Sciencementioning

confidence: 99%

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Functional suppression of E-cadherin by protein kinase Cδ

Chen

2009

Journal of Cell Science

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“…Overexpression of EGFR and its downstream pathways, including ras-MEK-ERK and PI3K-AKT, are linked to advanced prostate cancer, especially hormoneindependent disease (19). It has been reported that EGFR was highly expressed in DU145 and PC3 cell lines and these cell lines were responsive to EGF stimulation (20). Furthermore, signaling through MAPK pathway may in turn promote phosphorylation of EGFR itself and accelerate the turnover of this receptor.…”

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microRNA-133 inhibits cell proliferation, migration and invasion in prostate cancer cells by targeting the epidermal growth factor receptor

Tao

Wu²,

et al. 2012

Oncol Rep

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Abstract.It has been shown that regulation of EGFR expression in prostate cancer cells is mostly at the transcriptional level. microRNA-133 (miR-133) has long been recognized as a muscle-specific miRNA which may regulate myoblast differentiation and participate in many myogenic diseases. Recently, it has been reported that miR-133 is also involved in other tumors, such as bladder cancer, esophageal cancer and may regulate cell motility in these cancer cells. In the present study, we examined the expression and effects of miR-133 in two hormone-insensitive prostate cancer cell lines. The expression of miR-133a and miR-133b were analyzed by quantitative RT-PCR. After transfection of miR-133a and miR-133b, cell viability assay, luciferase assay, western blot analysis, cell migration and invasion assay were conducted in DU145 and PC3 cells. In this study, we showed that miR-133a and miR-133b are expressed at the detection limit in two hormoneinsensitive prostate cancer cell lines, PC3 and DU145. Ectopic expression of miR-133 inhibited cell proliferation, migration and invasion in these cells. We also provide the first evidence that miR-133 may target EGFR. Our study provided the first glimpse of the functional role of miR-133 in two hormoneindependent prostate cancer cell lines. These results may add to our knowledge on the molecular basis of prostate cancer progression.

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Rottlerin inhibits migration of follicular thyroid carcinoma cells by PKCδ‐independent destabilization of the focal adhesion complex

Lin¹,

Lin²,

Chen³

et al. 2010

J of Cellular Biochemistry

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This study examined the effect of rottlerin on the focal adhesion-mediated cell migration of CGTH W-2 human follicular thyroid carcinoma cells. Rottlerin (10 microM) resulted in decreased adhesion of CGTH W-2 cells to matrix substance, which was correlated with metastatic potential. Rottlerin treatment also resulted in a marked reduction in the migration of CGTH W-2 cells. Protein levels of integrin beta1, FAK, and paxillin were decreased by rottlerin. Consistent with this, immunostaining of FAK, vinculin, and paxillin revealed disassembly of the focal adhesions. Disruption of actin stress fibers was noted, which was compatible with reduced expression levels and activities of Rac-1 and Rho. The effect of rottlerin on cell migration was not attributable to inhibition of PKCdelta activity since siRNA knockdown of PKCdelta did not recapitulate the effects of rottlerin on cell adhesion and migration. Furthermore, activation of PKCdelta by phorbol esters failed to restore the rottlerin-inhibited migratory ability. The mitochondrial uncoupler, carbonylcyanide-4-(trifluoromethoxy)-phenylhydrazone, was able to mimic several rottlerin's effects. In summary, we demonstrated that rottlerin inhibits the migration of CGTH W-2 cells by disassembly of focal adhesion complexes in a PKCdelta-independent manner, and might play as a mitochondrial uncoupler role in these events.

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Protein kinase Cδ signaling downstream of the EGF receptor mediates migration and invasiveness of prostate cancer cells

Cited by 55 publications

References 31 publications

Functional suppression of E-cadherin by protein kinase Cδ

Functional suppression of E-cadherin by protein kinase Cδ

microRNA-133 inhibits cell proliferation, migration and invasion in prostate cancer cells by targeting the epidermal growth factor receptor

Rottlerin inhibits migration of follicular thyroid carcinoma cells by PKCδ‐independent destabilization of the focal adhesion complex

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