Activation of Nuclear Factor κB by Somatostatin Type 2 Receptor in Pancreatic Acinar AR42J Cells Involves Gα₁₄ and Multiple Signaling Components

Medications targeting the somatostatin type 2 receptor (SSTR2) have been employed for pancreatic inflammations and cancers, possibly via the regulation of the transcription factor nuclear factor κB (NFκB). Here we demonstrate that in tumoral pancreatic acinar AR42J cells, activation of SSTR2 leads to stimulation of the inhibitor κB kinase (IKK)/NFκB signaling cascade via pertussis toxin-insensitive G proteins in a time- and dose-dependent manner. The inability of G_q/11 and G_12/13 proteins to activate IKK/NFκB by SSTR2 in transfected human embryonic kidney 293 cells and the lack of Gα₁₆ in AR42J cells suggested a possible role of Gα₁₄ in mediating SSTR2-induced responses. This regulatory role of Gα₁₄ was further confirmed by the activation of IKK and NFκB in human embryonic kidney 293 cells expressing SSTR2 and Gα₁₄ upon induction. The stimulatory effect of Gβ₁γ₂ and the abrogation by overexpressing transducin confirmed the participation of Gβγ in SSTR2-mediated IKK/NFκB activation. By the application of specific inhibitors and dominant negative mutants, phospholipase Cβ, protein kinase C, and calmodulin-dependent kinase II were shown to be involved in SSTR2-induced responses. Inhibition of c-Src and numerous intermediates, including Ras, Raf-1 kinase, MEK1/2, along with the extracellular signal-regulated kinase cascade attenuated somatostatin-mediated IKK/NFκB activation. Although c-Jun N-terminal kinase and p38 mitogen-activated protein kinase (MAPK) were also stimulated by SSTR2, suppression of these two MAPKs was ineffective in altering the somatostatin-mediated responses. Similar results were also obtained using AR42J cells. These data suggest that activation of the IKK/NFκB signaling cascade by SSTR2 requires a complicated network consisting of Gα₁₄ and multiple intermediates.