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

Abstract

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]

Protein Kinase D1 Suppresses Epithelial-to-Mesenchymal Transition through Phosphorylation of Snail

“…In addition, activation of PKD1 by bryostatin 1 can increase the colocalization of Snail and 14-3-3σ in the cytoplasm, particularly in the perinuclear areas (white arrow in Supplementary Fig. S1C), a pattern similar to the accumulation of activated PKD1 (41).…”

Protein Kinase D Signaling in Cancer

“…Recent data suggest that PKD1 may be crucial for cell-cell adhesion and linking adhesion complexes to the actin cytoskeleton [ 24,145,146 ] . The formation of E-cadherin/ b -catenin complexes at the cell junctions plays an important role in maintaining cell integrity, polarity, and morphogenesis [ 145 ] , and an aberrant expression or localization of the components of this complex has been associated with cancer progression and metastasis.…”

“…The formation of E-cadherin/ b -catenin complexes at the cell junctions plays an important role in maintaining cell integrity, polarity, and morphogenesis [ 145 ] , and an aberrant expression or localization of the components of this complex has been associated with cancer progression and metastasis. Phosphorylation of E-cadherin or b -catenin results in increased stabilization of the cadherin-catenin complex and increases cell-cell adhesion in adherens junctions [ 147,148 ] .…”

“…Expression of active PKD1 in prostate cancer cells stabilizes its interaction with E-cadherin and represses b -catenin-induced transcriptional activity [ 152 ] . Moreover, the activation of PKD1 with bryostatin 1, a natural macrocyclic lactone with antineoplastic properties in many tumors, induces a co-localization of the cytoplasmatic pool of b -catenin with PKD1 and proteins involved in vesicular traffi cking [ 145 ] . PKD1 was also linked to an integrin-mediated cell adhesion to extracellular matrix.…”

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

“…Earlier studies show that PKD1 has a role in cell growth, gene expression, survival, motility, protein trafficking and lymphocyte biology (Wang, 2006;Jaggi et al, 2007;Du et al, 2009). 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).…”