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      Lysophosphatidic Acid Induces MDA-MB-231 Breast Cancer Cells Migration through Activation of PI3K/PAK1/ERK Signaling

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          Abstract

          Background

          Enhanced motility of cancer cells is a critical step in promoting tumor metastasis. Lysophosphatidic acid (LPA), representing the major mitogenic activity in serum, stimulates migration in various types of cancer cells. However, the underlying signaling mechanisms for LPA-induced motility of cancer cells remain to be elucidated.

          Methodology/Principal Findings

          In this study, we found that LPA dose-dependently stimulated migration of MDA-MB-231 breast cancer cells, with 10 µM being the most effective. LPA also increased ERK activity and the MEK inhibitor U0126 could block LPA-induced ERK activity and cell migration. In addition, LPA induced PAK1 activation while ERK activation and cell migration were inhibited by ectopic expression of an inactive mutant form of PAK1 in MDA-MB-231 cells. Furthermore, LPA increased PI3K activity, and the PI3K inhibitor LY294002 inhibited both LPA-induced PAK1/ERK activation and cell migration. Moreover, in the breast cancer cell, LPA treatment resulted in remarkable production of reactive oxygen species (ROS), while LPA-induced ROS generation, PI3K/PAK1/ERK activation and cell migration could be inhibited by N-acetyl-L-Cysteine, a scavenger of ROS.

          Conclusions/Significance

          Taken together, this study identifies a PI3K/PAK1/ERK signaling pathway for LPA-stimulated breast cancer cell migration. These data also suggest that ROS generation plays an essential role in the activation of LPA-stimulated PI3K/PAK1/ERK signaling and breast cancer cell migration. These findings may provide a basis for designing future therapeutic strategy for blocking breast cancer metastasis.

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          Most cited references50

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          Biology of the p21-activated kinases.

          The p21-activated kinases (PAKs) 1-3 are serine/threonine protein kinases whose activity is stimulated by the binding of active Rac and Cdc42 GTPases. Our understanding of the regulation and biology of these important signaling proteins has increased tremendously since their discovery in the mid-1990s. PAKs 1-3 are activated by a variety of GTPase-dependent and -independent mechanisms. This complexity reflects the contributions of PAK function in many cellular signaling pathways and the need to carefully control PAK action in a highly localized manner. PAKs serve as important regulators of cytoskeletal dynamics and cell motility, transcription through MAP kinase cascades, death and survival signaling, and cell-cycle progression. Consequently, PAKs have also been implicated in a number of pathological conditions and in cell transformation. We propose here a key role for PAK action in coordinating the dynamics of the actin and microtubule cytoskeletons during directional motility of cells, as well as in other functions requiring cytoskeletal polarization.
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            p21-activated kinases in cancer.

            The pivotal role of kinases in signal transduction and cellular regulation has lent them considerable appeal as pharmacological targets across a broad spectrum of cancers. p21-activated kinases (Paks) are serine/threonine kinases that function as downstream nodes for various oncogenic signalling pathways. Paks are well-known regulators of cytoskeletal remodelling and cell motility, but have recently also been shown to promote cell proliferation, regulate apoptosis and accelerate mitotic abnormalities, which results in tumour formation and cell invasiveness. Alterations in Pak expression have been detected in human tumours, which makes them an attractive new therapeutic target.
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              Reactive oxygen species in tumor progression.

              The generation of reactive oxygen radicals in mammalian cells profoundly affects numerous critical cellular functions, and the absence of efficient cellular detoxification mechanisms which remove these radicals can result in several human diseases. Growing evidence suggests that reactive oxygen species (ROS) within cells act as second messengers in intracellular signaling cascades which induce and maintain the oncogenic phenotype of cancer cells. ROS are tumorigenic by virtue of their ability to increase cell proliferation, survival, cellular migration, and also by inducing DNA damage leading to genetic lesions that initiate tumorigenicity and sustain subsequent tumor progression. However, it is also known that ROS can induce cellular senescence and cell death and can therefore function as anti-tumorigenic agents. Therefore, the mechanisms by which cells respond to reactive oxygen species depends on the molecular background of cell and tissues, the location of ROS production and the concentration of individual ROS species. Carcinoma cells produce ROS at elevated rates in vitro, and in vivo many tumors appear persistent to oxidative stress. Thus, the finding that a diet rich in antioxidants or the elimination of ROS by antioxidant compounds prevents the development of certain cancers provided the setting for subsequent investigation of the tumorigenic actions of reactive oxygen species. This review outlines the current knowledge on the various roles of ROS in tumor development and progression.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS One
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, USA )
                1932-6203
                2010
                30 December 2010
                : 5
                : 12
                : e15940
                Affiliations
                [1 ]Department of Physiology, Nanjing Medical University, Nanjing, China
                [2 ]Kangda College, Nanjing Medical University, Nanjing, China
                [3 ]Cancer Center, Nanjing Medical University, Nanjing, China
                [4 ]The Second Affiliated Hospital of Nanjing Medical University, Nanjing, China
                Florida International University, United States of America
                Author notes

                Conceived and designed the experiments: LG XL. Performed the experiments: JD CS ZH. Analyzed the data: YY YZ DZ. Contributed reagents/materials/analysis tools: JD. Wrote the paper: LG JD.

                Article
                PONE-D-10-00774
                10.1371/journal.pone.0015940
                3012724
                21209852
                d6bd732a-7249-4ca2-8f76-a81eb9ac5989
                Du et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
                History
                : 16 August 2010
                : 30 November 2010
                Page count
                Pages: 10
                Categories
                Research Article
                Biology
                Molecular Cell Biology
                Signal Transduction
                Signaling Cascades
                ERK signaling cascade
                Protein Kinase Signaling Cascade
                Medicine
                Obstetrics and Gynecology
                Breast Cancer
                Oncology
                Basic Cancer Research
                Metastasis
                Cancers and Neoplasms
                Breast Tumors

                Uncategorized
                Uncategorized

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