Role of SLC6A6 in promoting the survival and multidrug resistance of colorectal cancer

Sci Rep. 2014 Apr 30;4:4852. doi: 10.1038/srep04852.

Abstract

The treatment of colorectal cancer (CRC) might be improved by the identification of a signalling pathway that could be targeted with novel therapeutics. The results of this study indicate that the taurine transporter SLC6A6 is highly expressed in CRC cells compared with normal colonocytes. SLC6A6 knockdown (KD) attenuated cell survival and was accompanied by enhanced drug sensitivity to 5-fluorouracil (5-FU), doxycycline (DOX) and SN-38. Both the population frequency of the side population (SP) cells and their cancer stem cell (CSC)-like properties (such as tumour initiation, differentiation and chemoresistance) were abrogated by SLC6A6-KD. Conversely, SLC6A6 overexpression increased cell survival and the proportion of SP cells, enhancing multidrug resistance (MDR). Additionally, SLC6A6-siRNA treatment enhanced the cytotoxic effects of all 3 drugs, whereas the efficacy of ABCG2-siRNA treatment was limited to its 2 substrate drugs, DOX and SN-38. This study indicates that SLC6A6 plays an important role in the maintenance of CSC characteristics, thus promoting cell survival signalling and chemoresistance. Therefore, SLC6A6 inhibition may be a promising therapeutic strategy for refractory CRC.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily G, Member 2
  • ATP-Binding Cassette Transporters / genetics
  • ATP-Binding Cassette Transporters / metabolism
  • Animals
  • Cell Line, Tumor
  • Cell Survival / genetics
  • Colorectal Neoplasms / genetics*
  • Colorectal Neoplasms / metabolism
  • Colorectal Neoplasms / pathology
  • Disease Models, Animal
  • Drug Resistance, Multiple / genetics*
  • Drug Resistance, Neoplasm / genetics*
  • Female
  • Fluorouracil / metabolism
  • Fluorouracil / pharmacology
  • Gene Expression
  • Gene Expression Profiling
  • Gene Knockdown Techniques
  • Heterografts
  • Humans
  • Membrane Glycoproteins / genetics*
  • Membrane Glycoproteins / metabolism
  • Membrane Transport Proteins / genetics*
  • Membrane Transport Proteins / metabolism
  • Mice
  • Neoplasm Proteins / genetics
  • Neoplasm Proteins / metabolism
  • Neoplastic Stem Cells / drug effects
  • Neoplastic Stem Cells / metabolism
  • Phenotype
  • Side-Population Cells / drug effects
  • Side-Population Cells / metabolism
  • Signal Transduction

Substances

  • ABCG2 protein, human
  • ATP Binding Cassette Transporter, Subfamily G, Member 2
  • ATP-Binding Cassette Transporters
  • Membrane Glycoproteins
  • Membrane Transport Proteins
  • Neoplasm Proteins
  • taurine transporter
  • Fluorouracil