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