Protein kinase C μ is down-regulated in androgen-independent prostate cancer

Jaggi, Meena; Rao, P. S.; Smith, David J.; Hemstreet, George P.; Balaji, K.C.

doi:10.1016/s0006-291x(03)01161-6

Cited by 67 publications

(79 citation statements)

References 22 publications

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“…We have previously identified and confirmed the downregulation of PKD1 in the prostate cancer C4-2 cell line (25). We have also generated stable C4-2 transfectants with fulllength PKD1-GFP or GFP vector alone (23).…”

Section: Resultsmentioning

confidence: 78%

Bryostatin 1 modulates β-catenin subcellular localization and transcription activity through protein kinase D1 activation

Jaggi

Chauhan

et al. 2008

Molecular Cancer Therapeutics

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In recent years, the use of natural products for cancer prevention and treatment has received considerable attention. Bryostatin 1 is a natural macrocyclic lactone and a protein kinase D (PKD) modulator with potent antineoplastic properties that has been used to treat human cancers in clinical trials with limited success. Further understanding the mechanistic basis of Bryostatin 1 action may provide opportunities to improve clinical results of treatment with Bryostatin 1. We identified that PKD1, founding member of PKD family of serine/threonine kinases, modulates E-cadherin/B-catenin activity, which plays an important role in cell integrity, polarity, growth, and morphogenesis. An aberrant expression and localization of E-cadherin/B-catenin has been strongly associated with cancer progression and metastasis. In this study, we examined the effect of Bryostatin 1 treatment on PKD1 activation, B-catenin translocation and transcription activity, and malignant phenotype of prostate cancer cells. Initial activation of PKD1 with Bryostatin 1 leads to colocalization of the cytoplasmic pool of B-catenin with PKD1, trans-Golgi network markers, and proteins involved in vesicular trafficking. Activation of PKD1 by Bryostatin 1 decreases nuclear B-catenin expression and B-catenin/TCF transcription activity. Activation of PKD1 alters cellular aggregation and proliferation in prostate cancer cells associated with subcellular redistribution of E-cadherin and B-catenin. For the first time, we have identified that Bryostatin 1 modulates B-catenin signaling through PKD1, which identifies a novel mechanism to improve efficacy of Bryostatin 1 in clinical settings. [Mol Cancer Ther 2008;7(9):2703 -12]

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Section: Resultsmentioning

confidence: 78%

Bryostatin 1 modulates β-catenin subcellular localization and transcription activity through protein kinase D1 activation

Jaggi

Chauhan

et al. 2008

Molecular Cancer Therapeutics

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“…Down regulation of E-cadherin is an early event in PC and therefore, study of E-cadherin expression in apparently localized PC biopsy specimens may help in identifying patients at higher risk of progression [Kuniyasu et al, 2003;Ohmori et al, 2006]. On the contrary, PKD1 is apparently unaltered in early PC is however down regulated in advanced PC [Jaggi et al, 2003]. While current understanding of PKD1 does not make it an ideal marker for biomarker evaluation, its interaction and ability to influence E-cadherin mediated functions establishes PKD1 as a potential therapeutic target.…”

Section: Discussionmentioning

confidence: 99%

β‐catenin mediates alteration in cell proliferation, motility and invasion of prostate cancer cells by differential expression of E‐cadherin and protein kinase D1

Syed

Mak

et al. 2007

J of Cellular Biochemistry

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We have previously demonstrated that Protein Kinase D1 (PKD1) interacts with E-cadherin and is associated with altered cell aggregation and motility in prostate cancer (PC). Because both PKD1 and E-cadherin are known to be dysregulated in PC, in this study we investigated the functional consequences of combined dysregulation of PKD1 and E-cadherin using a panel of human PC cell lines. Gainand loss of function studies were carried out by either transfecting PC cells with fulllength E-cadherin and/or PKD1 cDNA or by protein silencing by siRNAs, respectively. We studied major malignant phenotypic characteristics including cell proliferation, motility, and invasion at the cellular level, which were corroborated with appropriate changes in representative molecular markers. Down regulation or ectopic expression of either E-cadherin or PKD1 significantly increased or decreased cell proliferation, motility, and invasion, respectively, and combined down regulation cumulatively influenced the effects. Loss of PKD1 or E-cadherin expression was associated with increased expression of the pro-survival molecular markers survivin, β-catenin, cyclin-D, and c-myc, whereas overexpression of PKD1 and/or E-cadherin resulted in an increase of caspases. The inhibitory effect of PKD1 and E-cadherin on cell proliferation was rescued by coexpression with β-catenin, suggesting that β-catenin mediates the effect of proliferation by PKD1 and E-cadherin. This study establishes the functional significance of combined dysregulation of PKD1 and E-cadherin in PC and that their effect on cell growth is mediated by β-catenin.

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“…Inhibition of PKD1 in PC cells reduces the effect of PKD1 activators on Hsp27 and p38 MAPK phosphorylation To confirm the specificity of PKD1 in mediating NT-, Bom-and bryostatin-1-induced Hsp27 phosphorylation at Ser82 and p38 MAPK in PC, LNCaP cells (known to express high levels of endogenous PKD1 (Jaggi et al, 2003)) were transfected with either targeted or nontargeted small hairpin RNA (shRNA) PKD1. PKD1 expression was inhibited by more than 70% using PKD1-targeted shRNA in LNCaP cells, and both nontargeted and PKD1-targeted shRNA-transfected LNCaP cells were stimulated with 20 nM NT, 10 nM Bom and with two doses (10 nM or 30 nM) of bryostatin-1.…”

Section: Hsp27 Mediates Repression Of Ar By Pkd1 In Pc Cells S Hassanmentioning

confidence: 99%

“…In intact cells, PKD1 is activated by phorbol esters, bryostatin-1 (a marine-derived macrolactone), G-protein-coupled receptor agonists, such as neurotensin (NT) and bombesin (Bom), and other growth factors (Rozengurt et al, 2005;Evans et al, 2008;Jaggi et al, 2008;Yuan and Rozengurt, 2008). We initially discovered that PKD1 is downregulated in advanced prostate cancer (PC), and later described its interaction with E-cadherin, b-catenin and androgen receptor (AR) (Jaggi et al, 2003(Jaggi et al, , 2005Mak et al, 2008;Syed et al, 2008). Two other independent studies have recently shown that heat shock protein (Hsp27) is a novel substrate of PKD1 (Doppler et al, 2005) and there is ligand-dependent interaction of Hsp27 and AR in PC cells (Zoubeidi et al, 2007).…”

Section: Introductionmentioning

confidence: 99%

Heat shock protein 27 mediates repression of androgen receptor function by protein kinase D1 in prostate cancer cells

et al. 2009

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We have previously shown that protein kinase D1 (PKD1), charter member of PKD protein family, is downregulated in advanced prostate cancer (PC) and influences androgen receptor (AR) function in PC cells. Other independent studies showed that serine 82 residue in heat shock protein 27 (Hsp27) undergoes substrate phosphorylation by PKD1 and is associated with nuclear transport of AR resulting in increased AR transcriptional activity. In this study, we show that PKD1 interacts and phosphorylates Hsp27 at Ser82 in PC cells, which is mediated by p38-dependent mitogen-activated protein kinase pathway and is necessary for PKD1 repression of AR transcriptional activity and androgen-dependent proliferation of PC cells. The study provides first in vivo evidence that Hsp27 is a mediator of repression of AR function by PKD1 in PC cells, thereby linking the data in the published literature.

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Protein kinase C μ is down-regulated in androgen-independent prostate cancer

Cited by 67 publications

References 22 publications

Bryostatin 1 modulates β-catenin subcellular localization and transcription activity through protein kinase D1 activation

Bryostatin 1 modulates β-catenin subcellular localization and transcription activity through protein kinase D1 activation

β‐catenin mediates alteration in cell proliferation, motility and invasion of prostate cancer cells by differential expression of E‐cadherin and protein kinase D1

Heat shock protein 27 mediates repression of androgen receptor function by protein kinase D1 in prostate cancer cells

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