title: Lysophosphatidic acid activates the RhoA and NF-κB through Akt/IκBα signaling and promotes prostate cancer invasion and progression by enhancing functional invadopodia formation.
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.
authors.affiliation: Department of Dental Hygiene, College of Health Science, Eulji University, Seongnam, Republic of Korea.
authors.forename: Young Sun
authors.initials: YS
authors.lastname: Hwang
authors.affiliation: Department of Genetic Engineering, Sungkyunkwan University, 2066, Seobu-Ro, Jangan Gu, Suwon City, Gyunggi Do, 164-19, Republic of Korea.
authors.forename: Jongsung
authors.initials: J
authors.lastname: Lee
authors.affiliation: Oral Cancer Research Institute, Yonsei University College of Dentistry, Seoul, Republic of Korea.|Department of Pathology, Yanbian University Hospital, Yanji City, Jilin Province, China.
authors.forename: Xianglan
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Pathology, Northwestern University, Feinberg School of Medicine, Chicago, IL, 60611, USA. p-lindholm@northwestern.edu.
authors.forename: Paul F
authors.initials: PF
authors.lastname: Lindholm
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D018450:Disease Progression; D005109:Extracellular Matrix / Q000378:metabolism; D064593:Heterografts; D006801:Humans; D008246:Lysophospholipids / Q000494:pharmacology*; D008297:Male; D016328:NF-kappa B / Q000378:metabolism*; D009361:Neoplasm Invasiveness; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D020742:rhoA GTP-Binding Protein / Q000378:metabolism*
chemical_list: D008246:Lysophospholipids; D016328:NF-kappa B; D051057:Proto-Oncogene Proteins c-akt; D020742:rhoA GTP-Binding Protein; C032881:lysophosphatidic acid
keywords: Invadopodia; Lysophosphatidic acid; NF-κB; Prostate cancer; RhoA