Specific targeting of Wnt/β-catenin signaling in human melanoma cells by a dietary triterpene lupeol.
Wingless (Wnt) signaling pathway regulates a variety of cellular processes including proliferation, differentiation, survival, apoptosis and cell motility. Aberrant activation of Wnt/β-catenin pathway has been observed in approximately one-third of melanomas and this subset has very poor prognosis suggesting that targeting Wnt signaling could be a promising strategy against this subtype. Mel 928 and Mel 1241 melanoma cells representative of cells with constitutive activation of Wnt/β-catenin signaling pathway and Mel 1011 representative of cells that lack this pathway were treated with a dietary triterpene lupeol and its effects on growth, proliferation, β-catenin transcriptional activity and Wnt target genes were determined both in vitro and in vivo. Lupeol treatment to Mel 928 and Mel 1241 but not Mel 1011 cells resulted in a dose-dependent (i) decrease in cell viability, (ii) induction of apoptosis, (iii) decrease in colonogenic potential, (iv) decrease in β-catenin transcriptional activity and (v) decrease in the expression of Wnt target genes. Most importantly, lupeol restricted the translocation of β-catenin from the cytoplasm to the nucleus. Lupeol also decreased the growth of Mel 928 but not Mel 1011-derived tumors implanted in the athymic nude mice. The decrease in Mel 928-derived tumor growth was associated with a decrease in the expression of Wnt target genes c-myc, cyclin D1, proliferation markers proliferating cell nuclear antigen and Ki-67 and invasion marker osteopontin. We suggest that lupeol alone or as an adjuvant to current therapies could be developed as an agent for the management of human melanomas harboring constitutive Wnt/β-catenin signaling.
Tarapore
Rohinton S
RS
Molecular and Environmental Toxicology Center, University of Wisconsin, Madison, WI 53706, USA.
Siddiqui
Imtiaz A
IA
Saleem
Mohammad
M
Adhami
Vaqar M
VM
Spiegelman
Vladimir S
VS
Mukhtar
Hasan
H
D000818:Animals; D016588:Anticarcinogenic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D053148:Caspase 3 / Q000378:metabolism; D053179:Caspase 7 / Q000378:metabolism; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008297:Male; D008545:Melanoma / Q000188:drug therapy* / Q000473:pathology; D051379:Mice; D053978:Pentacyclic Triterpenes / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects*; D051153:Wnt Proteins / Q000037:antagonists & inhibitors* / Q000502:physiology; D023041:Xenograft Model Antitumor Assays; D051176:beta Catenin / Q000037:antagonists & inhibitors* / Q000502:physiology; D000094042:Lupanes
D016588:Anticarcinogenic Agents; D053148:Caspase 3; D053179:Caspase 7; D053978:Pentacyclic Triterpenes; D051153:Wnt Proteins; D051176:beta Catenin; C010480:lupeol; D000094042:Lupanes