Tumor Biology

, Volume 37, Issue 5, pp 6775–6785 | Cite as

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
Original Article


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.


Lysophosphatidic acid Prostate cancer Invadopodia RhoA NF-κB 



Lysophosphatidic acid


Epithelial-mesenchymal transition


Extracellular matrix


Pertussis toxin




G protein-coupled receptors


Micro-computed tomography.



We thank Hyung-Kwan Kim (Yonsei University College of Dentistry, Korea) for his expert technical assistance with the animal studies. This research was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology (2015R1D1A1A01056946).

Compliance with ethical standards

Conflicts of interest



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Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2015

Authors and Affiliations

  • Young Sun Hwang
    • 1
  • Jongsung Lee
    • 2
  • Xianglan Zhang
    • 3
    • 4
  • Paul F. Lindholm
    • 5
  1. 1.Department of Dental Hygiene, College of Health ScienceEulji UniversitySeongnamSouth Korea
  2. 2.Department of Genetic EngineeringSungkyunkwan UniversitySuwon CitySouth Korea
  3. 3.Oral Cancer Research InstituteYonsei University College of DentistrySeoulSouth Korea
  4. 4.Department of PathologyYanbian University HospitalYanji CityChina
  5. 5.Department of PathologyNorthwestern University, Feinberg School of MedicineChicagoUSA

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