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

  • Original Article
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Tumor Biology

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.

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Abbreviations

LPA:

Lysophosphatidic acid

EMT:

Epithelial-mesenchymal transition

ECM:

Extracellular matrix

PTX:

Pertussis toxin

ATX:

Autotaxin

GPCRs:

G protein-coupled receptors

μCT:

Micro-computed tomography.

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Acknowledgments

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).

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Authors and Affiliations

  1. Department of Dental Hygiene, College of Health Science, Eulji University, Seongnam, South Korea

    Young Sun Hwang

  2. Department of Genetic Engineering, Sungkyunkwan University, 2066, Seobu-Ro, Jangan Gu, Suwon City, Gyunggi Do, 164-19, South Korea

    Jongsung Lee

  3. Oral Cancer Research Institute, Yonsei University College of Dentistry, Seoul, South Korea

    Xianglan Zhang

  4. Department of Pathology, Yanbian University Hospital, Yanji City, Jilin Province, China

    Xianglan Zhang

  5. Department of Pathology, Northwestern University, Feinberg School of Medicine, Chicago, IL, 60611, USA

    Paul F. Lindholm

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  1. Young Sun Hwang
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Correspondence to Paul F. Lindholm.

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YS Hwang and JS Lee: These authors contributed equally to this work

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Hwang, Y.S., Lee, J., Zhang, X. et al. Lysophosphatidic acid activates the RhoA and NF-κB through Akt/IκBα signaling and promotes prostate cancer invasion and progression by enhancing functional invadopodia formation. Tumor Biol. 37, 6775–6785 (2016). https://doi.org/10.1007/s13277-015-4549-x

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