We have analyzed the effects of
fluvastatin, an inhibitor of the
enzyme 3-hydroxy-3-methylglutaryl-coenzyme A (
HMG-CoA) reductase involved in
mevalonate synthesis, on human NK cell-mediated anti-
tumor cytolysis.
Fluvastatin inhibited the activation of the small guanosin
triphosphate binding protein (
GTP) RhoA and the consequent actin redistribution induced by
ligation of LFA1 involved in NK-
tumor target cell adhesion. Also,
fluvastatin reduced
ganglioside M1 rafts formation triggered through the engagement of NK cell activating receptors as FcγRIIIA (CD16), NKG2D and DNAM1. Cytolysis of
tumor targets was inhibited up to 90% when NK cells were cultured with
fluvastatin by affecting i) receptor-mediated increase of the intracellular free
calcium concentration, ii) activation of akt1/PKB and iii)
perforin and
granzyme release.
Fluvastatin displayed a stronger inhibiting effect on NKG2D, DNAM1, 2B4, NKp30, NKp44 and NKp46 than on CD16-mediated NK cell triggering. This was in line with the impairment of surface expression of all these receptors but not of CD16. Remarkably,
fluvastatin did not affect the expression of the inhibiting receptors CD94, KIR2D and LAIR1. FasL release elicited by either NK-
tumor cell interaction or CD16 or NKG2D engagement, as well as FasL-mediated killing, were not sensitive to
fluvastatin. Moreover, TNFα secretion triggered in NK cells upon incubation with
tumor target cells or engagement of
NKG2D receptor was not impaired in
fluvastatin-treated NK cells. Likewise, antibody dependent cellular cytotoxicity (ADCC) triggered through FcγRIIIA engagement with the humanized
monoclonal antibody rituximab or
trastuzumab was only marginally affected in
fluvastatin-treated NK cells. Altogether these findings suggest that interference with
mevalonate synthesis impairs activation and assembly of cytoskeleton, degranulation and cytotoxic effect of perforins and
granzyme but not FasL- and TNFα-mediated cytotoxicity.