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 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.—Venkatraman, G., Benesch, M. G. K., Tang, X., Dewald, J., McMullen, T. P. W., Brindley, D. N., Lysophosphatidate signaling stabilizes Nrf2 and increases the expression of genes involved in drug resistance and oxidative stress responses: implications for cancer treatment. FASEB J. 29, 772–785 (2015). www.fasebj.org