Curcumin as an agent for cancer prevention in colorectal cancer


Year:

Session type:

Theme:

Sam Khan1,Ankur Karmokar1,Zahirah Sidat2,Nalini Foreman1,David Moore3,Anne Thomas1,Karen Brown1
1Leicester Cancer Research Centre, Robert Kilpatrick Clinical Sciences Building, University of Leicester, Leicester,2Hope Clinical Trials Facility, Leicester Royal Infirmary, Leicester,3University College London Hospitals NHS Foundation Trust, London

Abstract

Background

Over 25% of patients with colorectal cancer (CRC) present with metastatic disease for which the 5yr survival is 8%. Innovative prevention strategies to delay CRC are needed. Targeting cancer stem-like cells (CSCs) is a promising strategy. Nanog is crucial for the self-renewal of CSCs. Nanog is not expressed in most tissues, including normal adult stem-cells, representing a therapeutic target specific to cancer cells. Curcumin inhibits proliferation of CSCs derived from CRC and adenomas. In NOD/SCID mice bearing xenografts from patient-derived CRC CSCs, curcumin significantly inhibited tumour growth and improved survival. The mechanism of action of curcumin is investigated.

Method

  1. Affinity pull-down assays with curcumin-coupled beads were carried out. The effect of curcumin on Nanog-DNA interaction was evaluated using electrophoretic mobility shift and reporter assays.
  2. The effect of curcumin on protein and gene expression of Nanog was assessed via western blot and RNASeq respectively. Nanog expression and proliferation following curcumin treatment was measured using flow cytometry.  
  3. Patient tissues were subtyped, profiled for Nanog, explanted and treated with curcumin. Subsequently, changes in Nanog expression, proliferation and differentiation (Mucin-2) were assessed.

Results

  1. Curcumin binds Nanog (106±8μM), specifically the homeodomain, inhibits Nanog-DNA interaction and significantly decreases Nanog transcriptional activity.
  2. HCT116GFP/Nanog colospheres were more sensitive to curcumin treatment than control cells. Nanog protein was reduced following curcumin treatment. RNASeq analysis is ongoing. Nanog+ and Nanog+Ki67+ populations were significantly reduced following treatment.
  3. Nanog expression was significantly higher in adenoma and CRC tissues compared to normal tissues. Following curcumin treatment Nanog+ and Nanog+Ki67+ expression was reduced in the 16/20 patient samples, across all consensus molecular subtypes. Curcumin reduced Nanog expression with a concurrent increase in Mucin-2 (non-CSC) expression.

Conclusion

Nanog is targeted by curcumin in adenoma and CRC tissues. Nanog may serve as a biomarker in clinical trials to identify individuals most amenable to curcumin for the prevention of CRC.