title: The role of RGD-tagged helical rosette nanotubes in the induction of inflammation and apoptosis in human lung adenocarcinoma cells through the P38 MAPK pathway.
abstract: The rosette nanotubes (RNTs) are a class of biologically inspired, self-assembling, metal-free, hydrophilic nanotubes, which hold tremendous potential as targeted drug delivery vehicles. We investigated the cell signaling events caused by lysine-functionalized RNTs (K-RNT) co-assembled with Arg-Gly-Asp-Ser-Lys-functionalized RNTs (RGDSK-RNT) for induction of inflammation and apoptosis in human adenocarcinoma (Calu-3) cells. When co-assembled in a ratio of 1:10 microM these composite RNTs (referred to as RGDSK/K-RNTs) rapidly induced phosphorylation of P38 mitogen-activated protein kinase (MAPK) within 2 min. Higher concentrations of RGDSK/K-RNTs (>10:100 microM) resulted in a P38 MAPK-dependent increase in secretion of TNF-alpha. RGDSK/K-RNTs (1:10-40:400 microM) also caused a concentration- and P38 MAPK-dependent increase in caspase-3 activity and DNA fragmentation in Calu-3 cells at 18 h of exposure. Over-expression of pro-apoptotic genes including caspase-3, BAK1, CIDEB, TP53BP2, FAS, TNF and FASLG supported pro-apoptotic behaviors of these RNTs. We conclude that RGDSK/K-RNTs induce phosphorylation of P38 MAPK, which regulate secretion of TNF-alpha, activation of caspase-3 and apoptosis in Calu-3 cells. These results suggest that the RNTs could be used as a drug to induce apoptosis in cancer cells or as a versatile platform to deliver a variety of biologically active molecules for cancer therapy.
authors.affiliation: Department of Veterinary Biomedical Sciences, University of Saskatchewan, 52 Campus Drive, Saskatoon, SK S7N 1L7, Canada. sarabjeet.singh@usask.ca
authors.forename: Sarabjeet S
authors.initials: SS
authors.lastname: Suri
authors.forename: Felaniaina
authors.initials: F
authors.lastname: Rakotondradany
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Myles
authors.forename: Hicham
authors.initials: H
authors.lastname: Fenniri
authors.forename: Baljit
authors.initials: B
authors.lastname: Singh
mesh_terms: D000230:Adenocarcinoma / Q000473:pathology; D017209:Apoptosis; D053148:Caspase 3 / Q000032:analysis / Q000378:metabolism; D045744:Cell Line, Tumor; D053938:DNA Fragmentation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects; D005456:Fluorescent Dyes / Q000378:metabolism; D006801:Humans; D007211:Indoles / Q000378:metabolism; D007249:Inflammation / Q000139:chemically induced*; D008175:Lung Neoplasms / Q000473:pathology; D008958:Models, Molecular; D043942:Nanotubes / Q000737:chemistry*; D009842:Oligopeptides / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D010766:Phosphorylation; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
chemical_list: D005456:Fluorescent Dyes; D007211:Indoles; D009842:Oligopeptides; D014409:Tumor Necrosis Factor-alpha; C007293:DAPI; C047981:arginyl-glycyl-aspartic acid; C046617:arginyl-glycyl-aspartyl-serine; D048051:p38 Mitogen-Activated Protein Kinases; D053148:Caspase 3