Inhibition of NFkappaB and pancreatic cancer cell and tumor growth by curcumin is dependent on specificity protein down-regulation.
Curcumin activates diverse anticancer activities that lead to inhibition of cancer cell and tumor growth, induction of apoptosis, and antiangiogenic responses. In this study, we observed that curcumin inhibits Panc28 and L3.6pL pancreatic cancer cell and tumor growth in nude mice bearing L3.6pL cells as xenografts. In addition, curcumin decreased expression of p50 and p65 proteins and NFkappaB-dependent transactivation and also decreased Sp1, Sp3, and Sp4 transcription factors that are overexpressed in pancreatic cancer cells. Because both Sp transcription factors and NFkappaB regulate several common genes such as cyclin D1, survivin, and vascular endothelial growth factor that contribute to the cancer phenotype, we also investigated interactions between Sp and NFkappaB transcription factors. Results of Sp1, Sp3, and Sp4 knockdown by RNA interference demonstrate that both p50 and p65 are Sp-regulated genes and that inhibition of constitutive or tumor necrosis factor-induced NFkappaB by curcumin is dependent on down-regulation of Sp1, Sp3, and Sp4 proteins by this compound. Curcumin also decreased mitochondrial membrane potential and induced reactive oxygen species in pancreatic cancer cells, and this pathway is required for down-regulation of Sp proteins in these cells, demonstrating that the mitochondriotoxic effects of curcumin are important for its anticancer activities.
Department of Veterinary Physiology and Pharmacology, Texas A&M University, College Station, Texas 77843, USA.
Indira
I
Jutooru
Gayathri
G
Chadalapaka
Ping
P
Lei
Stephen
S
Safe
D000818:Animals; D015153:Blotting, Western; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003474:Curcumin / Q000494:pharmacology / Q000627:therapeutic use*; D019938:Cyclin D1 / Q000235:genetics; D024202:Electrophoretic Mobility Shift Assay; D004594:Electrophysiology; D005260:Female; D005434:Flow Cytometry; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000235:genetics; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D007150:Immunohistochemistry; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D051379:Mice; D008819:Mice, Nude; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism*; D016133:Polymerase Chain Reaction; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species / Q000378:metabolism; D051703:Sp Transcription Factors / Q000235:genetics / Q000378:metabolism*; D016329:Sp1 Transcription Factor / Q000235:genetics / Q000378:metabolism; D051705:Sp3 Transcription Factor / Q000235:genetics / Q000378:metabolism; D051706:Sp4 Transcription Factor / Q000235:genetics; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000235:genetics; D023041:Xenograft Model Antitumor Assays
D016328:NF-kappa B; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D051703:Sp Transcription Factors; D016329:Sp1 Transcription Factor; D051706:Sp4 Transcription Factor; D014409:Tumor Necrosis Factor-alpha; D042461:Vascular Endothelial Growth Factor A; D019938:Cyclin D1; D051705:Sp3 Transcription Factor; D006861:Hydrogen Peroxide; D040281:Vascular Endothelial Growth Factor Receptor-1; D003474:Curcumin