title: Bryostatin 1 modulates beta-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/beta-catenin activity, which plays an important role in cell integrity, polarity, growth, and morphogenesis. An aberrant expression and localization of E-cadherin/beta-catenin has been strongly associated with cancer progression and metastasis. In this study, we examined the effect of Bryostatin 1 treatment on PKD1 activation, beta-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 beta-catenin with PKD1, trans-Golgi network markers, and proteins involved in vesicular trafficking. Activation of PKD1 by Bryostatin 1 decreases nuclear beta-catenin expression and beta-catenin/TCF transcription activity. Activation of PKD1 alters cellular aggregation and proliferation in prostate cancer cells associated with subcellular redistribution of E-cadherin and beta-catenin. For the first time, we have identified that Bryostatin 1 modulates beta-catenin signaling through PKD1, which identifies a novel mechanism to improve efficacy of Bryostatin 1 in clinical settings.
authors.affiliation: Cancer Biology Research Center, Department of OBGYN and Basic Biomedical Science, Sanford Research/University of South Dakota, Sanford School of Medicine, University of South Dakota, 1400 West 22nd Street, Sioux Falls, SD 57105, USA. meena.jaggi@usd.edu
authors.forename: Meena
authors.initials: M
authors.lastname: Jaggi
authors.forename: Subhash C
authors.initials: SC
authors.lastname: Chauhan
authors.forename: Cheng
authors.initials: C
authors.lastname: Du
authors.forename: K C
authors.initials: KC
authors.lastname: Balaji