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

C. Mahanivong, H. M. Chen, S. W. Yee, Z. K. Pan, Zheng Dong, Shuang Huang

Research output: Contribution to journalArticle

52 Citations (Scopus)

Abstract

We reported previously that a signaling pathway consisting of G i-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.

Original languageEnglish (US)
Pages (from-to)1273-1280
Number of pages8
JournalOncogene
Volume27
Issue number9
DOIs
StatePublished - Feb 21 2008

Fingerprint

Complement Factor B
Plasminogen Activators
Urokinase-Type Plasminogen Activator
Ovarian Neoplasms
Protein Kinase C
Up-Regulation
Protein C Inhibitor
Protein Kinase Inhibitors
lysophosphatidic acid
ras Proteins
Mutant Proteins
Protein Isoforms

Keywords

  • LPA
  • NF-κB
  • Ovarian cancer
  • uPA

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

Cite this

Protein kinase Cα-CARMA3 signaling axis links Ras to NF-κB for lysophosphatidic acid-induced urokinase plasminogen activator expression in ovarian cancer cells. / Mahanivong, C.; Chen, H. M.; Yee, S. W.; Pan, Z. K.; Dong, Zheng; Huang, Shuang.

In: Oncogene, Vol. 27, No. 9, 21.02.2008, p. 1273-1280.

Research output: Contribution to journalArticle

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abstract = "We reported previously that a signaling pathway consisting of G i-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 G{\"o}6976 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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