Hyaluronan suppresses prostate tumor cell proliferation through diminished expression of N-cadherin and aberrant growth factor receptor signaling

Alamelu G. Bharadwaj, Nathaniel P. Goodrich, Caitlin O. McAtee, Katie Haferbier, Gregory G Oakley, James K Wahl, Melanie A. Simpson

Research output: Contribution to journalArticle

14 Citations (Scopus)

Abstract

Hyaluronan (HA) production has been functionally implicated in prostate tumorigenesis and metastasis. We previously used prostate tumor cells overexpressing the HA synthesizing enzyme HAS3 or the clinically relevant hyaluronidase Hyal1 to show that excess HA production suppresses tumor growth, while HA turnover accelerates spontaneous metastasis from the prostate. Here, we examined pathways responsible for effects of HAS3 and Hyal1 on tumor cell phenotype. Detailed characterization of cell cycle progression revealed that expression of Hyal1 accelerated cell cycle re-entry following synchronization, whereas HAS3 alone delayed entry. Hyal1 expressing cells exhibited a significant reduction in their ability to sustain ERK phosphorylation upon stimulation by growth factors, and in their expression of the cyclin-dependent kinase inhibitor p21. In contrast, HAS3 expressing cells showed prolonged ERK phosphorylation and increased expression of both p21 and p27, in asynchronous and synchronized cultures. Changes in cell cycle regulatory proteins were accompanied by HA-induced suppression of N-cadherin, while E-cadherin expression and -catenin expression and distribution remained unchanged. Our results are consistent with a model in which excess HA synthesis suppresses cell proliferation by promoting homotypic E-cadherin mediated cell-cell adhesion, consequently signaling to elevate cell cycle inhibitor expression and suppress G1- to S-phase transition.

Original languageEnglish (US)
Pages (from-to)1214-1225
Number of pages12
JournalExperimental Cell Research
Volume317
Issue number8
DOIs
StatePublished - May 1 2011

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Growth Factor Receptors
Hyaluronic Acid
Cadherins
Prostate
Cell Proliferation
Neoplasms
Cell Cycle
Phosphorylation
Cyclin-Dependent Kinase Inhibitor p21
Neoplasm Metastasis
Catenins
Cell Cycle Proteins
Hyaluronoglucosaminidase
Phase Transition
S Phase
Cell Adhesion
Intercellular Signaling Peptides and Proteins
Carcinogenesis
Phenotype
Enzymes

Keywords

  • Cadherin
  • Cell adhesion
  • Cell cycle
  • Hyaluronan
  • Integrin
  • Prostate cancer

ASJC Scopus subject areas

  • Cell Biology

Cite this

Hyaluronan suppresses prostate tumor cell proliferation through diminished expression of N-cadherin and aberrant growth factor receptor signaling. / Bharadwaj, Alamelu G.; Goodrich, Nathaniel P.; McAtee, Caitlin O.; Haferbier, Katie; Oakley, Gregory G; Wahl, James K; Simpson, Melanie A.

In: Experimental Cell Research, Vol. 317, No. 8, 01.05.2011, p. 1214-1225.

Research output: Contribution to journalArticle

Bharadwaj, Alamelu G. ; Goodrich, Nathaniel P. ; McAtee, Caitlin O. ; Haferbier, Katie ; Oakley, Gregory G ; Wahl, James K ; Simpson, Melanie A. / Hyaluronan suppresses prostate tumor cell proliferation through diminished expression of N-cadherin and aberrant growth factor receptor signaling. In: Experimental Cell Research. 2011 ; Vol. 317, No. 8. pp. 1214-1225.
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