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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References
Birgbauer E, Chun J . (2006). New developments in the biological functions of lysophospholipids. Cell Mol Life Sci 63: 2695–2701.
Corbalan-Garcia S, Gomez-Fernandez JC . (2006). Protein kinase C regulatory domains: the art of decoding many different signals in membranes. Biochim Biophys Acta 1761: 633–654.
Cummings R, Zhao Y, Jacoby D, Spannhake EW, Ohba M, Garcia JG et al. (2004). Protein kinase Cδ mediates lysophosphatidic acid-induced NF-kappaB activation and interleukin-8 secretion in human bronchial epithelial cells. J Biol Chem 279: 41085–41094.
Dlugosz AA, Cheng C, Williams EK, Dharia AG, Denning MF, Yuspa SH . (1994). Alterations in murine keratinocyte differentiation induced by activated rasHa genes are mediated by protein kinase Cα. Cancer Res 54: 6413–6420.
Do TV, Symowicz JC, Berman DM, Liotta LA, Petricoin III EF, Stack MS et al. (2007). Lysophosphatidic acid down-regulates stress fibers and up-regulates pro-matrix metalloproteinase-2 activation in ovarian cancer cells. Mol Cancer Res 5: 121–131.
Eder AM, Sasagawa T, Mao M, Aoki J, Mills GB . (2000). Constitutive and lysophosphatidic acid (LPA)-induced LPA production: role of phospholipase D and phospholipase A2. Clin Cancer Res 6: 2482–2491.
Fang X, Schummer M, Mao M, Yu S, Tabassam FH, Swaby R et al. (2002). Lysophosphatidic acid is a bioactive mediator in ovarian cancer. Biochim Biophys Acta 1582: 257–264.
Fischer K, Lutz V, Wilhelm O, Schmitt M, Graeff H, Heiss P et al. (1998). Urokinase induces proliferation of human ovarian cancer cells: characterization of structural elements required for growth factor function. FEBS Lett 438: 101–105.
Fishman DA, Liu Y, Ellerbroek SM, Stack MS . (2001). Lysophosphatidic acid promotes matrix metalloproteinase (MMP) activation and MMP-dependent invasion in ovarian cancer cells. Cancer Res 61: 3194–3199.
Grabiner BC, Blonska M, Lin PC, You Y, Wang D, Sun J et al. (2007). CARMA3 deficiency abrogates G protein-coupled receptor-induced NF-{kappa}B activation. Genes Dev 21: 984–996.
Hu YL, Tee MK, Goetzl EJ, Auersperg N, Mills GB, Ferrara N et al. (2001). Lysophosphatidic acid induction of vascular endothelial growth factor expression in human ovarian cancer cells. J Natl Cancer Inst 93: 762–768.
Kjoller L, Hall A . (2001). Rac mediates cytoskeletal rearrangements and increased cell motility induced by urokinase-type plasminogen activator receptor binding to vitronectin. J Cell Biol 152: 1145–1157.
Klemm S, Zimmermann S, Peschel C, Mak TW, Ruland J . (2007). Bcl10 and Malt1 control lysophosphatidic acid-induced NF-kappaB activation and cytokine production. Proc Natl Acad Sci USA 104: 134–138.
Konecny G, Untch M, Pihan A, Kimmig R, Gropp M, Stieber P et al. (2001). Association of urokinase-type plasminogen activator and its inhibitor with disease progression and prognosis in ovarian cancer. Clin Cancer Res 7: 1743–1749.
LaVallie ER, Chockalingam PS, Collins-Racie LA, Freeman BA, Keohan CC, Leitges M et al. (2006). Protein kinase Czeta is up-regulated in osteoarthritic cartilage and is required for activation of NF-kappaB by tumor necrosis factor and interleukin-1 in articular chondrocytes. J Biol Chem 281: 24124–24137.
Li H, Ye X, Mahanivong C, Bian D, Chun J, Huang S . (2005). Signaling mechanisms responsible for lysophosphatidic acid-induced urokinase plasminogen activator expression in ovarian cancer cells. J Biol Chem 280: 10564–10571.
Lucas PC, Yonezumi M, Inohara N, McAllister-Lucas LM, Abazeed ME, Chen FF et al. (2001). Bcl10 and MALT1, independent targets of chromosomal translocation in malt lymphoma, cooperate in a novel NF-kappa B signaling pathway. J Biol Chem 276: 19012–19019.
Matsumoto R, Wang D, Blonska M, Li H, Kobayashi M, Pappu B et al. (2005). Phosphorylation of CARMA1 plays a critical role in T Cell receptor-mediated NF-kappaB activation. Immunity 23: 575–585.
McAllister-Lucas LM, Inohara N, Lucas PC, Ruland J, Benito A, Li Q et al. (2001). Bimp1, a MAGUK family member linking protein kinase C activation to Bcl10-mediated NF-kappaB induction. J Biol Chem 276: 30589–30597.
Murthi P, Barker G, Nowell CJ, Rice GE, Baker MS, Kalionis B et al. (2004). Plasminogen fragmentation and increased production of extracellular matrix-degrading proteinases are associated with serous epithelial ovarian cancer progression. Gynecol Oncol 92: 80–88.
Pal S, Datta K, Khosravi-Far R, Mukhopadhyay D . (2001). Role of protein kinase Czeta in Ras-mediated transcriptional activation of vascular permeability factor/vascular endothelial growth factor expression. J Biol Chem 276: 2395–2403.
Perletti GP, Folini M, Lin HC, Mischak H, Piccinini F, Tashjian Jr AH . (1996). Overexpression of protein kinase C epsilon is oncogenic in rat colonic epithelial cells. Oncogene 12: 847–854.
Pustilnik TB, Estrella V, Wiener JR, Mao M, Eder A, Watt MA et al. (1999). Lysophosphatidic acid induces urokinase secretion by ovarian cancer cells. Clin Cancer Res 5: 3704–3710.
Schmalfeldt B, Kuhn W, Reuning U, Pache L, Dettmar P, Schmitt M et al. (1995). Primary tumor and metastasis in ovarian cancer differ in their content of urokinase-type plasminogen activator, its receptor, and inhibitors types 1 and 2. Cancer Res 55: 3958–3963.
Schwartz BM, Hong G, Morrison BH, Wu W, Baudhuin LM, Xiao YJ et al (2001). Lysophospholipids increase interleukin-8 expression in ovarian cancer cells. Gynecol Oncol 81: 291–300.
Sommer K, Guo B, Pomerantz JL, Bandaranayake AD, Moreno-Garcia ME, Ovechkina YL et al. (2005). Phosphorylation of the CARMA1 linker controls NF-kappaB activation. Immunity 23: 561–574.
Suzuki M, Kobayashi H, Kanayama N, Saga Y, Suzuki M, Lin CY et al. (2004). Inhibition of tumor invasion by genomic down-regulation of matriptase through suppression of activation of receptor-bound pro-urokinase. J Biol Chem 279: 14899–14908.
Tanyi JL, Morris AJ, Wolf JK, Fang X, Hasegawa Y, Lapushin R et al. (2003). The human lipid phosphate phosphatase-3 decreases the growth, survival, and tumorigenesis of ovarian cancer cells: validation of the lysophosphatidic acid signaling cascade as a target for therapy in ovarian cancer. Cancer Res 63: 1073–1082.
Wang D, You Y, Case SM, McAllister-Lucas LM, Wang L, DiStefano PS et al. (2002). A requirement for CARMA1 in TCR-induced NF-kappa B activation. Nat Immunol 3: 830–835.
Wang D, You Y, Lin PC, Xue L, Morris SW, Zeng H et al. (2007a). Bcl10 plays a critical role in NF-kappaB activation induced by G protein-coupled receptors. Proc Natl Acad Sci USA 104: 145–150.
Wang P, Wu X, Chen W, Liu J, Wang X . (2007b). The lysophosphatidic acid (LPA) receptors their expression and significance in epithelial ovarian neoplasms. Gynecol Oncol 104: 714–720.
Willis TG, Jadayel DM, Du MQ, Peng H, Perry AR, Abdul-Rauf M et al. (1999). Bcl10 is involved in t(1;14)(p22;q32) of MALT B cell lymphoma and mutated in multiple tumor types. Cell 96: 35–45.
Xu Y, Shen Z, Wiper DW, Wu M, Morton RE, Elson P et al. (1998). Lysophosphatidic acid as a potential biomarker for ovarian and other gynecologic cancers. JAMA 280: 719–723.
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This work was supported by the National Institute of Health Grant R01 CA93926.
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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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DOI: https://doi.org/10.1038/sj.onc.1210746
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