Sphingosine 1-phosphate antagonizes the effect of all-trans retinoic acid (ATRA) in a human colon cancer cell line by modulation of RARβ expression

Cancer Lett. 2012 Jun 28;319(2):182-189. doi: 10.1016/j.canlet.2012.01.012. Epub 2012 Jan 17.

Abstract

All-trans retinoic acid (ATRA) is a promising therapeutic agent, but exhibits low efficacy against human cancers. We investigated the effect of sphingosine-1-phosphate (S1P) on ATRA activity in human colon cancer HT-29 cells. S1P antagonized ATRA activity on HT-29 cell proliferation and retinoic acid receptor beta (RARβ) expression. S1P treatment or transient co-transfection with SphK2 expression vector antagonized ATRA-induced RARβ promoter activity. Proteasome inhibition prevented S1P-induced modulation of ATRA activity. Overall, S1P antagonized ATRA's inhibitory effects by down-regulating RARβ expression, likely via the proteasome-dependent pathway. Decreasing S1P production or inhibiting SphK2 activity could enhance the efficacy of retinoids in cancer treatments.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Proliferation / drug effects
  • Colonic Neoplasms / genetics
  • Down-Regulation
  • HT29 Cells
  • Humans
  • Leupeptins / pharmacology
  • Lysophospholipids / pharmacology*
  • Proteasome Inhibitors
  • Receptors, Retinoic Acid / genetics
  • Receptors, Retinoic Acid / metabolism*
  • Sphingosine / analogs & derivatives*
  • Sphingosine / pharmacology
  • Tretinoin / antagonists & inhibitors*
  • Tretinoin / pharmacology

Substances

  • Leupeptins
  • Lysophospholipids
  • Proteasome Inhibitors
  • Receptors, Retinoic Acid
  • retinoic acid receptor beta
  • sphingosine 1-phosphate
  • Tretinoin
  • Sphingosine
  • benzyloxycarbonylleucyl-leucyl-leucine aldehyde