Protein kinase C alpha-CARMA3 signaling axis links Ras to NF-kappa B for lysophosphatidic acid-induced urokinase plasminogen activator expression in ovarian cancer cells.
We reported previously that a signaling pathway consisting of G(i)-Ras-NF-kappaB 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)-kappaB 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 PKCalpha and Ras-PKCalpha interaction. Although constitutively active mutants of PKCalpha (a cPKC), PKCtheta (a novel PKC (nPKC)) and PKCzeta (an atypical PKC (aPKC)) were all able to activate NF-kappaB and upregulate uPA expression, only dominant-negative PKCalpha mutant attenuated LPA-induced NF-kappaB activation and uPA upregulation. These results suggest that PKCalpha, rather than PKC isoforms in other PKC classes, participates in LPA-induced NF-kappaB activation and uPA upregulation in ovarian cancer cells. To determine the signaling components downstream of PKCalpha 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 PKCalpha/CARMA3 signaling axis is important in LPA-induced ovarian cancer cell in vitro invasion.
Mahanivong
C
C
Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta, GA 30912, USA.
Chen
H M
HM
Yee
S W
SW
Pan
Z K
ZK
Dong
Z
Z
Huang
S
S
D051017:Apoptosis Regulatory Proteins / Q000502:physiology*; D053468:CARD Signaling Adaptor Proteins / Q000502:physiology*; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D008246:Lysophospholipids / Q000502:physiology*; D016328:NF-kappa B / Q000378:metabolism*; D009361:Neoplasm Invasiveness; D010051:Ovarian Neoplasms / Q000201:enzymology* / Q000473:pathology; D051571:Protein Kinase C-alpha / Q000037:antagonists & inhibitors / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*; D015854:Up-Regulation / Q000235:genetics; D014568:Urokinase-Type Plasminogen Activator / Q000096:biosynthesis / Q000235:genetics*; D018631:ras Proteins / Q000378:metabolism*
D051017:Apoptosis Regulatory Proteins; D053468:CARD Signaling Adaptor Proteins; C430880:CARD10 protein, human; D008246:Lysophospholipids; D016328:NF-kappa B; D051571:Protein Kinase C-alpha; D014568:Urokinase-Type Plasminogen Activator; D018631:ras Proteins; C032881:lysophosphatidic acid