Clusterin Silencing in Prostate Cancer Induces Matrix Metalloproteinases by an NF-κB-Dependent Mechanism

Martina Bonacini, Aide Negri, Pierpaola Davalli, Valeria Naponelli, Ileana Ramazzina, Chiara Lenzi, Saverio Bettuzzi, Federica Rizzi

Research output: Contribution to journalArticle

Abstract

Clusterin (CLU) is a stress-activated glycoprotein, whose expression is altered both in inflammation and cancer. Previously, we showed that abrogation of CLU expression in cancer-prone mice (TRAMP) results in the enhancement of tumor spreading and homing, concomitant with an enhanced expression of NF-B. In the present paper, we carried out an extensive experimental work by utilizing microarray gene expression data, as well as in vitro and in vivo models of prostate cancer (PCa). Our results demonstrated that (i) CLU expression is significantly downregulated in human PCa and inversely correlates with the expression of p65 in metastases; (ii) CLU overexpression in PCa cells reduces the Ser536 phosphorylation of p65, inhibits NF-B nuclear translocation, and reduces the transcription of matrix metalloproteinase-9 and metalloproteinase-2 (MMP-9 and MMP-2). Conversely, CLU silencing promotes NF-B activation and transcriptional upregulation of MMP-9; and (iii) expression and activity of MMP-2 and MMP-9 are increased in CLU-/- mice (CLUKO) and in TRAMP/CLUKO mice in comparison to their relative Clu+/+ littermates. Taken together, our data support the hypothesis that CLU downregulation, an early and relevant event in PCa onset, may inhibit NF-B activation and limit the execution of a transcriptional program that favor the disease progression towards a metastatic stage.

Original languageEnglish
Article number4081624
JournalJournal of Oncology
Volume2019
DOIs
Publication statusPublished - Dec 6 2019

ASJC Scopus subject areas

  • Oncology

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    Bonacini, M., Negri, A., Davalli, P., Naponelli, V., Ramazzina, I., Lenzi, C., Bettuzzi, S., & Rizzi, F. (2019). Clusterin Silencing in Prostate Cancer Induces Matrix Metalloproteinases by an NF-κB-Dependent Mechanism. Journal of Oncology, 2019, [4081624]. https://doi.org/10.1155/2019/4081624