title: Identification of galanin and its receptor GalR1 as novel determinants of resistance to chemotherapy and potential biomarkers in colorectal cancer.
abstract: OBJECTIVE
  A major factor limiting the effective clinical management of colorectal cancer (CRC) is resistance to chemotherapy. Therefore, the identification of novel, therapeutically targetable mediators of resistance is vital.
  
  
  METHODS
  We used a CRC disease-focused microarray platform to transcriptionally profile chemotherapy-responsive and nonresponsive pretreatment metastatic CRC liver biopsies and in vitro samples, both sensitive and resistant to clinically relevant chemotherapeutic drugs (5-FU and oxaliplatin). Pathway and gene set enrichment analyses identified candidate genes within key pathways mediating drug resistance. Functional RNAi screening identified regulators of drug resistance.
  
  
  RESULTS
  Mitogen-activated protein kinase signaling, focal adhesion, cell cycle, insulin signaling, and apoptosis were identified as key pathways involved in mediating drug resistance. The G-protein-coupled receptor galanin receptor 1 (GalR1) was identified as a novel regulator of drug resistance. Notably, silencing either GalR1 or its ligand galanin induced apoptosis in drug-sensitive and resistant cell lines and synergistically enhanced the effects of chemotherapy. Mechanistically, GalR1/galanin silencing resulted in downregulation of the endogenous caspase-8 inhibitor FLIP(L), resulting in induction of caspase-8-dependent apoptosis. Galanin mRNA was found to be overexpressed in colorectal tumors, and importantly, high galanin expression correlated with poor disease-free survival of patients with early-stage CRC.
  
  
  CONCLUSIONS
  This study shows the power of systems biology approaches to identify key pathways and genes that are functionally involved in mediating chemotherapy resistance. Moreover, we have identified a novel role for the GalR1/galanin receptor-ligand axis in chemoresistance, providing evidence to support its further evaluation as a potential therapeutic target and biomarker in CRC.
authors.affiliation: Queen's University Belfast, Belfast, Northern Ireland.
authors.forename: Leanne
authors.initials: L
authors.lastname: Stevenson
authors.forename: Wendy L
authors.initials: WL
authors.lastname: Allen
authors.forename: Richard
authors.initials: R
authors.lastname: Turkington
authors.forename: Puthen V
authors.initials: PV
authors.lastname: Jithesh
authors.forename: Irina
authors.initials: I
authors.lastname: Proutski
authors.forename: Gail
authors.initials: G
authors.lastname: Stewart
authors.forename: Heinz-Josef
authors.initials: HJ
authors.lastname: Lenz
authors.forename: Sandra
authors.initials: S
authors.lastname: Van Schaeybroeck
authors.forename: Daniel B
authors.initials: DB
authors.lastname: Longley
authors.forename: Patrick G
authors.initials: PG
authors.lastname: Johnston
mesh_terms: D054316:Biomarkers, Pharmacological / Q000378:metabolism; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000235:genetics; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005472:Fluorouracil / Q000008:administration & dosage; D019004:Galanin / Q000235:genetics* / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D045325:HCT116 Cells; D019073:HT29 Cells; D006801:Humans; D020411:Oligonucleotide Array Sequence Analysis; D009944:Organoplatinum Compounds / Q000008:administration & dosage; D000077150:Oxaliplatin; D034741:RNA, Small Interfering; D044091:Receptor, Galanin, Type 1 / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D054316:Biomarkers, Pharmacological; D009944:Organoplatinum Compounds; D034741:RNA, Small Interfering; D044091:Receptor, Galanin, Type 1; D000077150:Oxaliplatin; D019004:Galanin; D005472:Fluorouracil