Lysophosphatidic acid activates the RhoA and NF-κB through Akt/IκBα signaling and promotes prostate cancer invasion and progression by enhancing functional invadopodia formation

Young Sun Hwang, Jongsung Lee, Xianglan Zhang, Paul F. Lindholm*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

16 Scopus citations

Abstract

We have demonstrated previously that increased RhoA and nuclear factor (NF)-κB activities are associated with increased PC-3 prostate cancer cell invasion and that lysophosphatidic acid (LPA) significantly increases cancer invasion through RhoA and NF-κB activation. In this study, we identified the intermediate signaling molecules and specialized cell structures which are activated by LPA, resulting in enhanced cellular invasion. LPA-induced Akt and IκBα signaling pathways were necessary for RhoA and NF-κB activation, and these LPA effects were abolished by RhoA inhibition. Mice injected with PC-3 cells expressing dominant-negative RhoA N19 developed significantly less tumor growth compared with those injected with control (pcDNA 3.1). In addition, LPA treatment increased functional invadopodia formation. Activation of RhoA and NF-κB through the Akt and IκBα signaling pathway was required for LPA-stimulated gelatin degradation activity. LPA administration increased tumor growth and osteolytic lesions in a mouse xenograft model. These results indicate that LPA promotes PC-3 cell invasion by increasing functional invadopodia formation via upregulating RhoA and NF-κB signaling which contributes to prostate cancer progression. Therefore, the LPA and RhoA-NF-κB signaling axis may represent key molecular targets to inhibit prostate cancer invasion and progression.

Original languageEnglish (US)
Pages (from-to)6775-6785
Number of pages11
JournalTumor Biology
Volume37
Issue number5
DOIs
StatePublished - May 1 2016

Keywords

  • Invadopodia
  • Lysophosphatidic acid
  • NF-κB
  • Prostate cancer
  • RhoA

ASJC Scopus subject areas

  • Cancer Research

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