title: PKCζ Promotes Breast Cancer Invasion by Regulating Expression of E-cadherin and Zonula Occludens-1 (ZO-1) via NFκB-p65.
abstract: Atypical Protein Kinase C zeta (PKCζ) forms Partitioning-defective (PAR) polarity complex for apico-basal distribution of membrane proteins essential to maintain normal cellular junctional complexes and tissue homeostasis. Consistently, tumor suppressive role of PKCζ has been established for multiple human cancers. However, recent studies also indicate pro-oncogenic function of PKCζ without firm understanding of detailed molecular mechanism. Here we report a possible mechanism of oncogenic PKCζ signaling in the context of breast cancer. We observed that depletion of PKCζ promotes epithelial morphology in mesenchymal-like MDA-MB-231 cells. The induction of epithelial morphology is associated with significant upregulation of adherens junction (AJ) protein E-cadherin and tight junction (TJ) protein Zonula Occludens-1 (ZO-1). Functionally, depletion of PKCζ significantly inhibits invasion and metastatic progression. Consistently, we observed higher expression and activation of PKCζ signaling in invasive and metastatic breast cancers compared to non-invasive diseases. Mechanistically, an oncogenic PKCζ- NFκB-p65 signaling node might be involved to suppress E-cadherin and ZO-1 expression and ectopic expression of a constitutively active form of NFκB-p65 (S536E-NFκB-p65) significantly rescues invasive potential of PKCζ-depleted breast cancer cells. Thus, our study discovered a PKCζ - NFκB-p65 signaling pathway might be involved to alter cellular junctional dynamics for breast cancer invasive progression.
authors.affiliation: 1] The University of Kansas Cancer Center, University of Kansas Medical Center, Kansas City, KS 66160, USA [2] Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, KS 66160, USA [3] Institute of Reproductive Health &Regenerative Medicine, University of Kansas Medical Center, Kansas City, KS 66160, USA.
authors.forename: Arindam
authors.initials: A
authors.lastname: Paul
authors.affiliation: 1] The University of Kansas Cancer Center, University of Kansas Medical Center, Kansas City, KS 66160, USA [2] Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, KS 66160, USA.
authors.forename: Marsha
authors.initials: M
authors.lastname: Danley
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, KS 66160, USA.
authors.forename: Biswarup
authors.initials: B
authors.lastname: Saha
authors.affiliation: 1] The University of Kansas Cancer Center, University of Kansas Medical Center, Kansas City, KS 66160, USA [2] Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, KS 66160, USA.
authors.forename: Ossama
authors.initials: O
authors.lastname: Tawfik
authors.affiliation: 1] The University of Kansas Cancer Center, University of Kansas Medical Center, Kansas City, KS 66160, USA [2] Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, KS 66160, USA [3] Institute of Reproductive Health &Regenerative Medicine, University of Kansas Medical Center, Kansas City, KS 66160, USA.
authors.forename: Soumen
authors.initials: S
authors.lastname: Paul
mesh_terms: D021581:Active Transport, Cell Nucleus; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D015820:Cadherins / Q000235:genetics* / Q000378:metabolism; D002448:Cell Adhesion / Q000235:genetics; D045744:Cell Line, Tumor; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D009361:Neoplasm Invasiveness / Q000235:genetics; D009362:Neoplasm Metastasis; D011493:Protein Kinase C / Q000378:metabolism*; D015398:Signal Transduction; D019108:Tight Junctions / Q000378:metabolism; D051996:Transcription Factor RelA / Q000378:metabolism*; D014158:Transcription, Genetic; D062826:Zonula Occludens-1 Protein / Q000235:genetics* / Q000378:metabolism; D000099221:Protein Kinase C zeta
chemical_list: D015820:Cadherins; D011493:Protein Kinase C; D051996:Transcription Factor RelA; D062826:Zonula Occludens-1 Protein; D000099221:Protein Kinase C zeta