Abstract
Curcumin (diferuloylmethane), a polyphenol natural product
of the plant Curcuma longa, is undergoing early clinical trials
as a novel anticancer agent. However, the anticancer
mechanism of curcumin remains to be elucidated. Recently,
we have shown that curcumin inhibits phosphorylation of p70
S6kinase 1 (S6K1) and eukaryotic initiation factor 4E (eIF4E)
binding protein 1 (4E-BP1), two downstream effector molecules
of the mammalian target of rapamycin complex 1
(mTORC1) in numerous cancer cell lines. This study was
designed to elucidate the underlying mechanism. We observed
that curcumin inhibited mTORC1 signaling not by inhibition
of the upstream kinases, such as insulin-like growth factor 1
receptor (IGF-IR) and phosphoinositide-dependent kinase 1
(PDK1). Further, we found that curcumin inhibited mTORC1
signaling independently of protein phosphatase 2A (PP2A) or
AMP-activated protein kinase AMPK-tuberous sclerosis complex
(TSC). This is evidenced by the findings that curcumin
was able to inhibit phosphorylation of S6K1 and 4E-BP1 in the
cells pretreated with PP2A inhibitor (okadaic acid) or AMPK
inhibitor (compound C), or in the cells expressing dominantnegative
(dn) PP2A, shRNA to PP2A-A subunit, or dn-AMPKA.
Curcumin did not alter the TSC1/2 interaction. Knockout of
TSC2 did not affect curcumin inhibition of mTOR signaling.
Finally, we identified that curcumin was able to dissociate
raptor from mTOR, leading to inhibition of mTORC1 activity.
Therefore, our data indicate that curcumin may represent a
new class of mTOR inhibitor. [Cancer Res 2009;69(3):1000–8]