Curcumin has been reported to inhibit
inflammation,
tumor growth, angiogenesis and
metastasis by decreasing cell growth and by inducing apoptosis mainly through the inhibition of
nuclear factor kappa-B (NFκB), a master regulator of
inflammation. Recent reports also indicate potential metabolic effects of the
polyphenol, therefore we analyzed whether and how it affects the energy metabolism of
tumor cells. We show that
curcumin (10 µM) inhibits the activity of
ATP synthase in isolated mitochondrial membranes leading to a dramatic drop of
ATP and a reduction of oxygen consumption in in vitro and in vivo
tumor models. The effects of
curcumin on
ATP synthase are independent of the inhibition of NFκB since the IκB
Kinase inhibitor,
SC-514, does not affect
ATP synthase. The activities of the glycolytic
enzymes hexokinase,
phosphofructokinase,
pyruvate kinase and
lactate dehydrogenase are only slightly affected in a cell type-specific manner. The energy impairment translates into decreased
tumor cell viability. Moreover,
curcumin induces apoptosis by promoting the generation of
reactive oxygen species (ROS) and
malondialdehyde (MDA), a marker of
lipid oxidation, and autophagy, at least in part due to the activation of the
AMP-activated protein kinase (AMPK). According to the in vitro anti-
tumor effect,
curcumin (30 mg/kg
body weight) significantly delayed in vivo
cancer growth likely due to an energy impairment but also through the reduction of
tumor angiogenesis. These results establish the
ATP synthase, a central
enzyme of the cellular energy metabolism, as a target of the antitumoral
polyphenol leading to inhibition of
cancer cell growth and a general reprogramming of
tumor metabolism.