Lysophosphatidic acid activates the RhoA and NF-κB through Akt/IκBα signaling and promotes prostate cancer invasion and progression by enhancing functional invadopodia formation
- 293 Downloads
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.
KeywordsLysophosphatidic acid Prostate cancer Invadopodia RhoA NF-κB
G protein-coupled receptors
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
- 38.Radhakrishnan VM, Kojs P, Young G, Ramalingam R, Jagadish B, Mash EA, et al. pTyr421 cortactin is overexpressed in colon cancer and is dephosphorylated by curcumin: involvement of non-receptor type 1 protein tyrosine phosphatase (PTPN1). PLoS One. 2014;9:e85796.CrossRefPubMedPubMedCentralGoogle Scholar
- 58.Sims SM, Panupinthu N, Lapierre DM, Pereverzev A, Dixon SJ. Lysophosphatidic acid: a potential mediator of osteoblast-osteoclast signaling in bone. Biochim Biophys Acta. 1831;2013:109–16.Google Scholar