Curcumin could cure both NF2 and TSC (tuberous sclerosis) by "double" punches, knocking out PAK1 and TOR

This year a group at LSU in Louisiana found that Curcumin blocks the Raptor-TOR
(target of rapamycin) interaction which is essential for the activation
of TOR. The kinase TOR is abnormally activated when the tumor suppressors, TSC1 or
TSC2, dysfunction. The rare but formidable tumors associated with TSC (tuberous
sclerosis), where TSC1 or TSC2 dysfunctions, require TOR for their growth.
In animal experiments anti-TOR drugs such as rapamycin could suppress the
growth of TSC tumors, but none of these anti-TOR drugs is available on the
market as yet. However, the natural anti-cancer product "Curcumin" could
be potentially useful for the treatment of TSC, if its bioavailablity is
dramatically improved by either liposome, CD or propolis in the future, as
mentioned before.

Furthermore, two US groups, at Memorial Sloan-Kettering Cancer Center in
New York and MGH in Boston, reported recently that dysfunction of Merlin,
the NF2 gene product, which is the cause of NF2 tumors, also leads to the abnormal
activation of TOR. We found several years ago that Merlin is a direct PAK1
inhibitor (Hirokawa, Y. et al, 2004). It still remains to be clarified whether
the abnormal activation of TOR is through the kinase PAK1, which is abnormally
activated by the dysfunction of Merlin. Nevertheless, this finding suggests
that "Curcumin" could suppress the growth of NF2 tumors by at least two
ways, inactivating both PAK1 and TOR.

In this context, it would be of great interest to note that the tumor suppressor
"FOXO"/Daf-16 in a tiny nematode called C. elegans blocks the expression
of "Raptor", thereby inactivating "TOR". This potentially interesting finding
was reported in 2004 by Don Riddle's group at University of Missouri. Furthermore,
we recently found that the kinase PAK1 inactivates "FOXO" in this worm.

Thus, natural anti-PAK1 products such as Bio 30 and "Curcumin" would inactivate
"TOR" by reactivating "FOXO" at least in this worm. It would be certainly
worth testing whether this remains true with mammals, too.

To be continued

Beevers CS, Chen L, Liu L, Luo Y, Webster NJ, Huang S. (2009).
Curcumin disrupts the Mammalian target of rapamycin-raptor complex.
Cancer Res. 69, 1000-8.

Department of Biochemistry and Molecular Biology, Feist-Weiller Cancer Center,
Louisiana State University Health Sciences Center, Shreveport, Louisiana
71130-3932, USA.

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 S6
kinase 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 dominant-negative (dn) PP2A, shRNA
to PP2A-A subunit, or dn-AMPKalpha. 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.


Lopez-Lago MA, Okada T, Murillo MM, Socci N, Giancotti FG. (2009)
Loss of the tumor suppressor gene NF2, encoding merlin, constitutively activates
integrin-dependent mTORC1 signaling.
Mol Cell Biol. 29, 4235-49.

Cell Biology Program, Sloan-Kettering Institute for Cancer Research, Memorial
Sloan-Kettering Cancer Center, 1275 York Ave., New York, NY 10065, USA.

Integrin signaling promotes, through PAK1, phosphorylation and inactivation
of the tumor suppressor merlin, thus removing a block to mitogenesis in
normal cells. However, the biochemical function of merlin and the effector
pathways critical for the pathogenesis of malignant mesothelioma and other
NF2-related malignancies are not known. We report that integrin-specific
signaling promotes activation of mTORC1 and cap-dependent mRNA translation.

Depletion of merlin rescues mTORC1 signaling in cells deprived of anchorage
to a permissive extracellular matrix, suggesting that integrin signaling
controls mTORC1 through inactivation of merlin.

This signaling pathway controls translation of the cyclin D1 mRNA and, thereby,
cell cycle progression. In addition, it promotes cell survival. Analysis
of a panel of malignant mesothelioma cell lines reveals a strong correlation
between loss of merlin and activation of mTORC1.

Merlin-negative lines are sensitive to the growth-inhibitory effect of rapamycin,
and the expression of recombinant merlin renders them partially resistant
to rapamycin. Conversely, depletion of merlin restores rapamycin sensitivity
in merlin-positive lines. These results indicate that integrin-mediated
adhesion promotes mTORC1 signaling through the inactivation of merlin. Furthermore,
they reveal that merlin-negative mesotheliomas display unregulated mTORC1
signaling and are sensitive to rapamycin, thus providing a preclinical rationale
for prospective, biomarker-driven clinical studies of mTORC1 inhibitors
in these tumors.