TY - JOUR
T1 - Combining curcumin (diferuloylmethane) and heat shock protein inhibition for neurofibromatosis 2 treatment
T2 - Analysis of response and resistance pathways
AU - Angelo, Laura S.
AU - Wu, Ji Yuan
AU - Meng, Feng
AU - Sun, Michael
AU - Kopetz, Scott
AU - McCutcheon, Ian E.
AU - Slopis, John M.
AU - Kurzrock, Razelle
PY - 2011/11
Y1 - 2011/11
N2 - Neurofibromatosis type 2 (NF2) is a genetic condition characterized by inactivation of the NF2 tumor suppressor gene and the development of schwannomas. The NF2 gene product, merlin, is activated (dephosphorylated) by contact inhibition and promotes growth suppression. We investigated the effect of curcumin (diferuloylmethane), a molecule with anti-inflammatory and antitumorigenic properties, on human schwannoma cell growth and the regulation of merlin by curcumin in both NF2 cells and neuroblastoma (non-NF2) cells. Curcumin inhibited the growth of HEI-193 schwannoma cells in vitro and downregulated the phosphorylation of Akt and extracellular signal-regulated kinase 1/2. Curcumin also activated MYPT1-pp1δ (a merlin phosphatase), which was associated with dephosphorylation of merlin on serine 518, an event that results in the folding of merlin to its active conformation. In addition, curcumin induced apoptosis and generated reactive oxygen species in HEI-193 cells. Consequently, hsp70 was upregulated at the mRNA and protein levels, possibly serving as a mechanism of escape from curcumin-induced apoptosis and growth inhibition. Endogenous merlin and hsp70 proteins interacted in HEI-193 schwannoma and SK-N-AS neuroblastoma cells. The combination of curcumin and an hsp inhibitor synergistically suppressed schwannoma cell growth. Our results provide a rationale for combining curcumin and KNK437 in the treatment of NF2.
AB - Neurofibromatosis type 2 (NF2) is a genetic condition characterized by inactivation of the NF2 tumor suppressor gene and the development of schwannomas. The NF2 gene product, merlin, is activated (dephosphorylated) by contact inhibition and promotes growth suppression. We investigated the effect of curcumin (diferuloylmethane), a molecule with anti-inflammatory and antitumorigenic properties, on human schwannoma cell growth and the regulation of merlin by curcumin in both NF2 cells and neuroblastoma (non-NF2) cells. Curcumin inhibited the growth of HEI-193 schwannoma cells in vitro and downregulated the phosphorylation of Akt and extracellular signal-regulated kinase 1/2. Curcumin also activated MYPT1-pp1δ (a merlin phosphatase), which was associated with dephosphorylation of merlin on serine 518, an event that results in the folding of merlin to its active conformation. In addition, curcumin induced apoptosis and generated reactive oxygen species in HEI-193 cells. Consequently, hsp70 was upregulated at the mRNA and protein levels, possibly serving as a mechanism of escape from curcumin-induced apoptosis and growth inhibition. Endogenous merlin and hsp70 proteins interacted in HEI-193 schwannoma and SK-N-AS neuroblastoma cells. The combination of curcumin and an hsp inhibitor synergistically suppressed schwannoma cell growth. Our results provide a rationale for combining curcumin and KNK437 in the treatment of NF2.
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U2 - 10.1158/1535-7163.MCT-11-0243
DO - 10.1158/1535-7163.MCT-11-0243
M3 - Article
C2 - 21903608
AN - SCOPUS:81055124264
SN - 1535-7163
VL - 10
SP - 2094
EP - 2103
JO - Molecular cancer therapeutics
JF - Molecular cancer therapeutics
IS - 11
ER -