Identification of galanin and its receptor GalR1 as novel determinants of resistance to chemotherapy and potential biomarkers in colorectal cancer

Leanne Stevenson, Wendy L. Allen, Richard Turkington, Puthen V. Jithesh, Irina Proutski, Gail Stewart, Heinz Josef Lenz, Sandra Van Schaeybroeck, Daniel B. Longley, Patrick G. Johnston

Research output: Contribution to journalArticle

30 Citations (Scopus)

Abstract

Purpose: 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. Experimental design: 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 FLIPL, 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. Conclusion: 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.

Original languageEnglish
Pages (from-to)5412-5426
Number of pages15
JournalClinical Cancer Research
Volume18
Issue number19
DOIs
Publication statusPublished - 1 Oct 2012
Externally publishedYes

Fingerprint

Receptor, Galanin, Type 1
Galanin Receptors
Galanin
Colorectal Neoplasms
Biomarkers
Drug Resistance
Drug Therapy
oxaliplatin
Caspase 8
Apoptosis
Ligands
Focal Adhesions
Caspase Inhibitors
Systems Biology
Genetic Association Studies
Liver Neoplasms
G-Protein-Coupled Receptors
RNA Interference
Mitogen-Activated Protein Kinases
Fluorouracil

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Identification of galanin and its receptor GalR1 as novel determinants of resistance to chemotherapy and potential biomarkers in colorectal cancer. / Stevenson, Leanne; Allen, Wendy L.; Turkington, Richard; Jithesh, Puthen V.; Proutski, Irina; Stewart, Gail; Lenz, Heinz Josef; Van Schaeybroeck, Sandra; Longley, Daniel B.; Johnston, Patrick G.

In: Clinical Cancer Research, Vol. 18, No. 19, 01.10.2012, p. 5412-5426.

Research output: Contribution to journalArticle

Stevenson, L, Allen, WL, Turkington, R, Jithesh, PV, Proutski, I, Stewart, G, Lenz, HJ, Van Schaeybroeck, S, Longley, DB & Johnston, PG 2012, 'Identification of galanin and its receptor GalR1 as novel determinants of resistance to chemotherapy and potential biomarkers in colorectal cancer', Clinical Cancer Research, vol. 18, no. 19, pp. 5412-5426. https://doi.org/10.1158/1078-0432.CCR-12-1780
Stevenson, Leanne ; Allen, Wendy L. ; Turkington, Richard ; Jithesh, Puthen V. ; Proutski, Irina ; Stewart, Gail ; Lenz, Heinz Josef ; Van Schaeybroeck, Sandra ; Longley, Daniel B. ; Johnston, Patrick G. / Identification of galanin and its receptor GalR1 as novel determinants of resistance to chemotherapy and potential biomarkers in colorectal cancer. In: Clinical Cancer Research. 2012 ; Vol. 18, No. 19. pp. 5412-5426.
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AU - Proutski, Irina

AU - Stewart, Gail

AU - Lenz, Heinz Josef

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AU - Johnston, Patrick G.

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AB - Purpose: 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. Experimental design: 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 FLIPL, 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. Conclusion: 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.

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