Thioridazine inhibits self-renewal in breast cancer cells via DRD2-dependent STAT3 inhibition, but induces a G1 arrest independent of DRD2

J Biol Chem. 2018 Oct 12;293(41):15977-15990. doi: 10.1074/jbc.RA118.003719. Epub 2018 Aug 21.

Abstract

Thioridazine is an antipsychotic that has been shown to induce cell death and inhibit self-renewal in a broad spectrum of cancer cells. The mechanisms by which these effects are mediated are currently unknown but are presumed to result from the inhibition of dopamine receptor 2 (DRD2). Here we show that the self-renewal of several, but not all, triple-negative breast cancer cell lines is inhibited by thioridazine. The inhibition of self-renewal by thioridazine in these cells is mediated by DRD2 inhibition. Further, we demonstrate that DRD2 promotes self-renewal in these cells via a STAT3- and IL-6-dependent mechanism. We also show that thioridazine induces a G1 arrest and a loss in cell viability in all tested cell lines. However, the reduction in proliferation and cell viability is independent of DRD2 and STAT3. Our results indicate that although there are cell types in which DRD2 inhibition results in inhibition of STAT3 and self-renewal, the dramatic block in cancer cell proliferation across many cell lines caused by thioridazine treatment is independent of DRD2 inhibition.

Keywords: DRD2; G protein–coupled receptor (GPCR); G1 arrest; STAT3; apoptosis; cell proliferation; cell signaling; cell viability; dopamine receptor; interleukin 6 (IL-6); proliferation; self-renewal; thioridazine.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Apoptosis / drug effects
  • Breast Neoplasms / drug therapy*
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Cell Self Renewal / drug effects*
  • Cell Survival / drug effects
  • Chlorpromazine / pharmacology
  • Dopamine D2 Receptor Antagonists / pharmacology
  • G1 Phase Cell Cycle Checkpoints / drug effects*
  • Humans
  • Receptors, Dopamine D2 / metabolism*
  • STAT3 Transcription Factor / antagonists & inhibitors*
  • STAT3 Transcription Factor / metabolism
  • Thioridazine / pharmacology*

Substances

  • DRD2 protein, human
  • Dopamine D2 Receptor Antagonists
  • Receptors, Dopamine D2
  • STAT3 Transcription Factor
  • STAT3 protein, human
  • Thioridazine
  • Chlorpromazine