Somatostatin inhibits Akt phosphorylation and cell cycle entry, but not p42/p44 mitogen-activated protein (MAP) kinase activation in normal and tumoral pancreatic acinar cells
S. Charland et al., Somatostatin inhibits Akt phosphorylation and cell cycle entry, but not p42/p44 mitogen-activated protein (MAP) kinase activation in normal and tumoral pancreatic acinar cells, ENDOCRINOL, 142(1), 2001, pp. 121-128
Somatostatin, or its structural analog SMS 201-995 (SMS), is recognized to
exert a growth-inhibitory action in rat pancreas, but the cellular mechanis
ms are not completely understood. This study was undertaken to evaluate the
effect of SMS on p42/p44 MAP kinases and phosphatidylinositol 3-kinase act
ivation and to analyze expression of some cell cycle regulatory proteins in
relation to pancreatic acinar cell proliferation in vivo (rat pancreas), a
s well as in the well-established tumoral cell line AR4-2J. We herein repor
t that: 1) SMS inhibits caerulein-induced pancreatic weight and DNA content
and abolishes epidermal growth factor (EGF)-stimulated AR4-2J proliferatio
n; 2) SMS only moderately reduces the stimulatory effect of caerulein on p4
2/p44 MAP kinase activities in pancreas and has no effect on EGF-stimulated
MAP kinase activities in AR4-2J cells; 3) SMS repressed caerulein-induced
Akt activity in normal pancreas; 4) SMS has a strong inhibitory action on c
yclin E expression induced by caerulein in pancreas and EGF in AR4-2J cells
and as expected, the resulting cyclin E-associated cyclin-dependent kinase
(cdk)a activity, as well as pRb phosphorylation, are blunted by SMS treatm
ent in both models; and 5) SMS suppresses mitogen-induced p27(Kip1) down-re
gulation, as well as marginally induces p21(Cip) expression. Thus, our data
suggest that somatostatin-induced growth arrest is mediated by inhibition
of phosphatidylinositol 3-kinase pathway and by enhanced expression of p21(
Cip) and p27(Kip1), leading to repression of pRb phosphorylation and cyclin
E-cdk2 complex activity.