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Lysophosphatidate signaling stabilizes Nrf2 and increases the expression of genes involved in drug resistance and oxidative stress responses: implications for cancer treatment.

Authors
  • Venkatraman, Ganesh1
  • Benesch, Matthew G K1
  • Tang, Xiaoyun1
  • Dewald, Jay1
  • McMullen, Todd P W1
  • Brindley, David N2
  • 1 *Signal Transduction Research Group, Department of Biochemistry, University of Alberta, Edmonton, Alberta, Canada; and Department of Surgery, University of Alberta, WC Mackenzie Health Science Centre, Edmonton, Alberta, Canada. , (Canada)
  • 2 *Signal Transduction Research Group, Department of Biochemistry, University of Alberta, Edmonton, Alberta, Canada; and Department of Surgery, University of Alberta, WC Mackenzie Health Science Centre, Edmonton, Alberta, Canada [email protected] , (Canada)
Type
Published Article
Journal
The FASEB Journal
Publisher
Federation of American Society for Experimental Biology
Publication Date
Mar 01, 2015
Volume
29
Issue
3
Pages
772–785
Identifiers
DOI: 10.1096/fj.14-262659
PMID: 25398768
Source
Medline
Keywords
License
Unknown

Abstract

The present work elucidates novel mechanisms for lysophosphatidate (LPA)-induced chemoresistance using human breast, lung, liver, and thyroid cancer cells. LPA (0.5-10 μM) increased Nrf2 transcription factor stability and nuclear localization by ≤5-fold. This involved lysophosphatidate type 1 (LPA1) receptors as identified with 1 μM wls-31 (LPA1/2 receptor agonist) and blocking this effect with 20 μM Ki16425 (LPA1-3 antagonist, Ki = 0.34 μM). Knockdown of LPA1 by 50% to 60% with siRNA decreased Nrf2 stability and expressing LPA1, but not LPA2/3, in human HepG2 cells increased Nrf2 stabilization. LPA-induced Nrf2 expression increased transcription of multidrug-resistant transporters and antioxidant genes by 2- to 4-fold through the antioxidant response element. This protected cells from doxorubicin-induced death. This pathway was verified in vivo by orthotopic injection of 20,000 mouse 4T1 breast cancer cells into syngeneic mice. Blocking LPA production with 10 mg/kg per d ONO-8430506 (competitive autotaxin inhibitor, IC90 = 100 nM) decreased expression of Nrf2, multidrug-resistant transporters, and antioxidant genes in breast tumors by ≤90%. Combining 4 mg/kg doxorubicin every third day with ONO-8430506 synergistically decreased tumor growth and metastasis to lungs and liver by >70%, whereas doxorubicin alone had no significant effect. This study provides the first evidence that LPA increases antioxidant gene and multidrug-resistant transporter expression. Blocking this aspect of LPA signaling provides a novel strategy for improving chemotherapy.

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