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

The present work elucidates novel mechanisms for lysophosphatidate (LPA)-induced chemo-resistance 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 (LPA_1/2 receptor agonist) and blocking this effect with 20 µM Ki16425 (LPA_1-3 antagonist, K_i = 0.34 µM). Knockdown of LPA₁ by 50% to 60% with siRNA decreased Nrf2 stability and expressing LPA₁, but not LPA_2/3, in human HepG2 cells increased Nrf2 stabilization. LPA-induced Nrf 2 expression increased transcription of multidrug-resistant transporters and antioxi-dant 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 syn-geneic mice. Blocking LPA production with 10 mg/kg per d ONO-8430506 (competitive autotaxin inhibitor, IC₉₀ = 100 nM) decreased expression of Nrf 2, 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. [ABSTRACT FROM AUTHOR]