The prostate metastasis suppressor gene NDRG1 differentially regulates cell motility and invasion

Anup Sharma, Janet Mendonca, James Ying, Hea Soo Kim, James E. Verdone, Jelani C. Zarif, Michael Carducci, Hans-Joerg Hammers, Kenneth J. Pienta, Sushant Kachhap

Research output: Contribution to journalArticlepeer-review

Abstract

Experimental and clinical evidence suggests that N-myc downregulated gene 1 (NDRG1) functions as a suppressor of prostate cancer metastasis. Elucidating pathways that drive survival and invasiveness of NDRG1-deficient prostate cancer cells can help in designing therapeutics to target metastatic prostate cancer cells. However, the molecular mechanisms that lead NDRG1-deficient prostate cancer cells to increased invasiveness remain largely unknown. In this study, we demonstrate that NDRG1-deficient prostate tumors have decreased integrin expression and reduced cell adhesion and motility. Our data indicate that loss of NDRG1 differentially affects Rho GTPases. Specifically, there is a downregulation of active RhoA and Rac1 GTPases with a concomitant upregulation of active Cdc42 in NDRG1-deficient cells. Live cell imaging using a fluorescent sensor that binds to polymerized actin revealed that NDRG1-deficient cells have restricted actin dynamics, thereby affecting cell migration. These cellular and molecular characteristics are in sharp contrast to what is expected after loss of a metastasis suppressor. We further demonstrate that NDRG1-deficient cells have increased resistance to anoikis and increased invasiveness which is independent of its elevated Cdc42 activity. Furthermore, NDRG1 regulates expression and glycosylation of EMMPRIN, a master regulator of matrix metalloproteases. NDRG1 deficiency leads to an increase in EMMPRIN expression with a concomitant increase in matrix metalloproteases and thus invadopodial activity. Using a three-dimensional invasion assay and an in vivo metastasis assay for human prostate xenografts, we demonstrate that NDRG1-deficient prostate cancer cells exhibit a collective invasion phenotype and are highly invasive. Thus, our findings provide novel insights suggesting that loss of NDRG1 leads to a decrease in actinmediated cellular motility but an increase in cellular invasion, resulting in increased tumor dissemination which positively impacts metastatic outcome.

Original languageEnglish (US)
Pages (from-to)655-669
Number of pages15
JournalMolecular oncology
Volume11
Issue number6
DOIs
StatePublished - Jun 2017

Keywords

  • Actin cytoskeleton
  • Matrix metalloproteases
  • Metastasis
  • Prostate cancer

ASJC Scopus subject areas

  • Molecular Medicine
  • Genetics
  • Oncology
  • Cancer Research

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