SDF-1 chemokine signalling modulates the apoptotic responses to iron deprivation of clathrin-depleted DT40 cells

PLoS One. 2014 Aug 27;9(8):e106278. doi: 10.1371/journal.pone.0106278. eCollection 2014.

Abstract

We have previously deleted both endogenous copies of the clathrin heavy-chain gene in the chicken pre B-cell-line DT40 and replaced them with clathrin under the control of a tetracycline-regulatable promoter (Tet-Off). The originally derived cell-line DKO-S underwent apoptosis when clathrin expression was repressed. We have also described a cell-line DKO-R derived from DKO-S cells that was less sensitive to clathrin-depletion. Here we show that the restriction of transferrin uptake, resulting in iron deprivation, is responsible for the lethal consequence of clathrin-depletion. We further show that the DKO-R cells have up-regulated an anti-apoptotic survival pathway based on the chemokine SDF-1 and its receptor CXCR4. Our work clarifies several puzzling features of clathrin-depleted DT40 cells and reveals an example of how SDF-1/CXCR4 signalling can abrogate pro-apoptotic pathways and increase cell survival. We propose that the phenomenon described here has implications for the therapeutic approach to a variety of cancers.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / genetics*
  • Cell Line
  • Cell Survival
  • Chemokine CXCL12 / genetics
  • Chemokine CXCL12 / metabolism*
  • Chickens
  • Clathrin Heavy Chains / genetics*
  • Clathrin Heavy Chains / metabolism
  • Culture Media / chemistry
  • Gene Expression Profiling
  • Gene Expression Regulation
  • Iron Deficiencies*
  • Oligonucleotide Array Sequence Analysis
  • Precursor Cells, B-Lymphoid / cytology
  • Precursor Cells, B-Lymphoid / metabolism
  • Promoter Regions, Genetic / drug effects
  • Receptors, CXCR4 / genetics
  • Receptors, CXCR4 / metabolism*
  • Signal Transduction
  • Tetracycline / pharmacology
  • Transferrin / genetics
  • Transferrin / metabolism*

Substances

  • Chemokine CXCL12
  • Culture Media
  • Receptors, CXCR4
  • Transferrin
  • Clathrin Heavy Chains
  • Tetracycline