7 research outputs found
Changes in Sodium Pump Expression Dictate the Effects of Ouabain on Cell Growth*
Here we show that ouabain-induced cell growth regulation is intrinsically
coupled to changes in the cellular amount of Na/K-ATPase via the
phosphoinositide 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR)
pathway. Ouabain increases the endocytosis and degradation of Na/K-ATPase in
LLC-PK1, human breast (BT20), and prostate (DU145) cancer cells. However,
ouabain stimulates the PI3K/Akt/mTOR pathway and consequently up-regulates the
expression of Na/K-ATPase in LLC-PK1 but not BT20 and DU145 cells. This
up-regulation is sufficient to replete the plasma membrane pool of Na/K-ATPase
and to stimulate cell proliferation in LLC-PK1 cells. On the other hand,
ouabain causes a gradual depletion of Na/K-ATPase and an increased expression
of cell cycle inhibitor p21cip, which consequently
inhibits cell proliferation in BT20 and DU145 cells. Consistently, we observe
that small interfering RNA-mediated knockdown of Na/K-ATPase is sufficient to
induce the expression of p21cip and slow the proliferation
of LLC-PK1 cells. Moreover, this knockdown converts the growth stimulatory
effect of ouabain to growth inhibition in LLC-PK1 cells. Mechanistically, both
Src and caveolin-1 are required for ouabain-induced activation of Akt and
up-regulation of Na/K-ATPase. Furthermore, inhibition of the PI3K/Akt/mTOR
pathway by rapamycin completely blocks ouabain-induced expression of
Na/K-ATPase and converts ouabain-induced growth stimulation to growth
inhibition in LLC-PK1 cells. Taken together, we conclude that changes in the
expression of Na/K-ATPase dictate the growth regulatory effects of ouabain on
cells