title: Riproximin's activity depends on gene expression and sensitizes PDAC cells to TRAIL.
abstract: Riproximin (Rpx) is a type II ribosome inactivating protein, which was investigated for its activity in pancreatic ductal adenocarcinoma (PDAC) in a panel of 17 human and rat PDAC cell lines and in rat pancreatic cancer liver metastasis. Cytotoxicity in response to Rpx was determined by MTT assay, apoptosis by flow cytometry and qRT-PCR for apoptosis related genes, and the modulation of the transcriptome was monitored by micro array analysis. The combination effect of Rpx and TRAIL was assessed by MTT assay. Rpx showed high but varying cytotoxicity in PDAC cells. Based on overall gene expression, the sensitivity of these cells was linked to genes involved in apoptosis. Furthermore, based on the affinity of Rpx for CEA, the expression of carcinoembryonic antigen-related cell adhesion molecule (CEACAM) genes was significantly related to Rpx's cytotoxicity in cells with CEACAM gene expression. Exposure of Suit2-007 cells to Rpx induced the mRNA expression of members of signaling pathways initiating from most death receptors, and down modulation of TRAIL. Apoptosis was increased as shown by FACS analysis. Combination of Rpx with TRAIL resulted in a synergistic cytotoxic effect in human Suit2-007 and rat ASML cells, as evidenced by a 6-fold lower tumor cell survival than expected from an additive combination effect. Treatment of BDX rats bearing intra-portally implanted Suit2-007 cells showed a highly significant anticancer effect and indicated an application of Rpx against pancreatic cancer metastasis to the liver. These data favor further evaluation of Rpx as anticancer agent in PDAC.
authors.affiliation: Toxicology and Chemotherapy Unit; German Cancer Research Center (DKFZ); Heidelberg, Germany.
authors.forename: Hassan
authors.initials: H
authors.lastname: Adwan
authors.affiliation: Toxicology and Chemotherapy Unit; German Cancer Research Center (DKFZ); Heidelberg, Germany.
authors.forename: Ahmed
authors.initials: A
authors.lastname: Murtaja
authors.affiliation: Toxicology and Chemotherapy Unit; German Cancer Research Center (DKFZ); Heidelberg, Germany.
authors.forename: Khamael
authors.initials: K
authors.lastname: Kadhim Al-Taee
authors.affiliation: Toxicology and Chemotherapy Unit; German Cancer Research Center (DKFZ); Heidelberg, Germany.
authors.forename: Asim
authors.initials: A
authors.lastname: Pervaiz
authors.affiliation: Division of Biostatistics; Statistics for Translational Oncology; DKFZ; Heidelberg, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Hielscher
authors.affiliation: Toxicology and Chemotherapy Unit; German Cancer Research Center (DKFZ); Heidelberg, Germany.
authors.forename: Martin R
authors.initials: MR
authors.lastname: Berger
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D021441:Carcinoma, Pancreatic Ductal / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004357:Drug Synergism; D005638:Fruit / Q000737:chemistry; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy / Q000556:secondary; D031656:Olacaceae / Q000737:chemistry*; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D010940:Plant Proteins / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000494:pharmacology / Q000627:therapeutic use*; D014158:Transcription, Genetic
chemical_list: D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; D010940:Plant Proteins; D053221:TNF-Related Apoptosis-Inducing Ligand; C511795:riproximin protein, Ximenia americana
keywords: TRAIL; pancreatic ductal adenocarcinoma; riproximin; synergistic cytotoxicity; type II ribosome inactivating protein