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Role of lysophosphatidic acid in mitogenic responses
Author(s) -
zhang zhihong,
Hamilton Renae C,
Meier Kathryn E
Publication year - 2006
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.20.4.a697
Subject(s) - lysophosphatidic acid , autocrine signalling , epidermal growth factor , mapk/erk pathway , protein kinase b , microbiology and biotechnology , cell migration , cell growth , cell culture , cancer cell , receptor , biology , signal transduction , cancer research , chemistry , cell , medicine , cancer , biochemistry , genetics
Lysophosphatidic acid (LPA) refers to a family of small phospholipid mediators that bind to G‐protein‐coupled receptors. Responses of carcinoma cells to LPA include cell proliferation, survival, and migration. The purpose of the present study was to evaluate the role of LPA in human breast cancer cells. Specifically, the ability of LPA antagonists to affect the pro‐mitogenic actions of epidermal growth factor (EGF) was investigated. Two human breast cancer cell lines were used, MCF‐7 and MDA‐MB‐231. Both cell lines express mRNA for LPA 1 , LPA 2 , and LPA 3 , G protein‐coupled receptors for LPA. At 10μM, 18:1 LPA potentiates both directed (chemotactic) and random (chemokinetic) migration of MDA‐MB‐231 cells but has no effect on migration of MCF‐7 cells. Both MCF‐7 and MDA‐MB‐231 cells generate LPA; LPA levels in medium are increased by exogenous 18:1 LPA and by EGF. Both MCF‐7 and MDA‐MB‐231 cells proliferate in response to EGF and LPA. LPA and EGF stimulate the activation of Erk and Akt kinases in both cell lines. LPA‐induced activations of Erk and Akt kinases, as well as proliferation, are inhibited by Ki16425 and VPC32183, antagonists for LPA 1 /LPA 3. Interestingly, Ki16425 and VPC32183 also inhibit EGF‐induced activation of Akt (MDA‐MB‐231 and MCF‐7) and Erk (MCF‐7). These studies suggest a potential role for LPA as an autocrine mediator of mitogenic signaling in breast cancer cells. (Supported by DAMD17‐01‐1‐0730)