Curcumin downregulates the constitutive activity of NF-kappaB and induces apoptosis in novel mouse melanoma cells.
Melanoma, the most deadly form of skin cancer, is very aggressive and resistant to present therapies. The transcription factor nuclear factor-kappa B (NF-kappaB) has been reported to be constitutively active in many types of cancer. Constitutively active NF-kappaB seen in melanoma likely plays a central role in cell survival and growth. We have established and characterized novel cell lines from our murine melanoma model. Here we report the constitutive activity of NF-kappaB in these melanoma-derived cells, as shown by electrophoretic mobility shift assay and reporter assays. We hypothesized that agents that inhibit NF-kappaB may also inhibit cell proliferation and may induce apoptosis in such melanoma cells. Curcumin has been shown to inhibit NF-kappaB activity in several cell types. In our system, curcumin selectively inhibited growth of melanoma cells, but not normal melanocytes. Curcumin induced melanoma cells to undergo apoptosis, as shown by caspase-3 activation, inversion of membrane phosphatidyl serine, and increases in cells in the sub-G1 phase. A curcumin dose-dependent inhibition of NF-kappaB-driven reporter activity correlated with decreased levels of phospho-IkappaBalpha, and decreased expression of NF-kappaB-target genes COX-2 and cyclin D1. This study demonstrates that the use of cells from our model system can facilitate studies of signaling pathways in melanoma. We furthermore conclude that curcumin, a natural and safe compound, inhibits NF-kappaB activity and the expression of its downstream target genes, and also selectively induces apoptosis of melanoma cells but not normal melanocytes. These encouraging in-vitro results support further investigation of curcumin for treatment of melanoma in vivo.
Marín
Yarí E
YE
Susan Lehman Cullman Laboratory for Cancer Research, Department of Chemical Biology, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ, USA.
Wall
Brian A
BA
Wang
Su
S
Namkoong
Jin
J
Martino
Jeffrey J
JJ
Suh
Junghan
J
Lee
Hwa Jin
HJ
Rabson
Arnold B
AB
Yang
Chung S
CS
Chen
Suzie
S
Ryu
Jae-Ha
JH
D000818:Animals; D017304:Annexin A5 / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D053148:Caspase 3 / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D003474:Curcumin / Q000494:pharmacology*; D056741:Cyclin D; D016213:Cyclins / Q000235:genetics / Q000378:metabolism; D051546:Cyclooxygenase 2; D015536:Down-Regulation; D024202:Electrophoretic Mobility Shift Assay; D016193:G1 Phase / Q000187:drug effects; D008156:Luciferases / Q000378:metabolism; D008546:Melanoma, Experimental / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism*; D012878:Skin Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D014407:Tumor Cells, Cultured
D017304:Annexin A5; D000970:Antineoplastic Agents; D056741:Cyclin D; D016213:Cyclins; D016328:NF-kappa B; D008156:Luciferases; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D053148:Caspase 3; D003474:Curcumin