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Protein kinase Cα-CARMA3 signaling axis links Ras to NF-κB for lysophosphatidic acid-induced urokinase plasminogen activator expression in ovarian cancer cells

Abstract

We reported previously that a signaling pathway consisting of Gi-Ras-NF-κB mediates lysophosphatidic acid (LPA)-induced urokinase plasminogen activator (uPA) upregulation in ovarian cancer cells. However, it is not clear what signaling components link Ras to nuclear factor (NF)-κB for this LPA-induced event. In the present study, we found that treatment of protein kinase C (PKC) inhibitors including conventional PKC (cPKC) inhibitor Gö6976 abolished LPA-induced uPA upregulation in ovarian cancer cell lines tested, indicating the importance of cPKC activity in this LPA-induced event. Indeed, LPA stimulation led to the activation of PKCα and Ras–PKCα interaction. Although constitutively active mutants of PKCα (a cPKC), PKCθ (a novel PKC (nPKC)) and PKCζ (an atypical PKC (aPKC)) were all able to activate NF-κB and upregulate uPA expression, only dominant-negative PKCα mutant attenuated LPA-induced NF-κB activation and uPA upregulation. These results suggest that PKCα, rather than PKC isoforms in other PKC classes, participates in LPA-induced NF-κB activation and uPA upregulation in ovarian cancer cells. To determine the signaling components downstream of PKCα mediating LPA-induced uPA upregulation, we showed that forced expression of dominant-negative CARMA3 or silencing CARMA3, Bcl10 and MALT1 with specific siRNAs diminished these LPA-induced events. Furthermore, we demonstrated that PKCα/CARMA3 signaling axis is important in LPA-induced ovarian cancer cell in vitro invasion.

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Acknowledgements

This work was supported by the National Institute of Health Grant R01 CA93926.

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Correspondence to S Huang.

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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc).

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Mahanivong, C., Chen, H., Yee, S. et al. Protein kinase Cα-CARMA3 signaling axis links Ras to NF-κB for lysophosphatidic acid-induced urokinase plasminogen activator expression in ovarian cancer cells. Oncogene 27, 1273–1280 (2008). https://doi.org/10.1038/sj.onc.1210746

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