Enhancement of Drug Resistance by Lysophosphatidic Acid Receptor-3 in Mouse Mammary Tumor FM3A Cells

Abstract

Lysophosphatidic acid (LPA) acts as a simple phospholipid that interacts with G protein-coupled transmembrane LPA receptors. Recently, it has been reported that each LPA receptor plays different biological roles in acquisition of the malignant property of tumor cells. In this study, to assess the involvement of LPA receptor-3 (LPA3) in cell survival after treatment with anticancer drugs, we generated Lpar3-expressing FM3A-a3A9 cells from mouse mammary tumor FM3A cells and examined the cell survival rate after treatment with anticancer drugs compared with Lpar3-unexpressing cells. Cells were treated with 0.005 to 10 μM of cisplatin (CDDP) or doxorubicin (DOX) for 3 days. For the CDDP and DOX treatments, the cell survival rate of FM3A-a3A9 cells was significantly higher than that of Lpar3-unexpressing cells. The expression level of the Mdr1a gene in FM3A-a3A9 cells was higher than that of Lpar3-unexpressing cells, whereas no significant difference in multidrug resistance 1b (Mdr1b) and glutathione S-transferase mu1 (Gstm1) expressions was found. These results suggest that LPA3 may enhance the cell survival rate after treatment with anticancer drugs in mouse mammary tumor cells, correlating with increased expression of the Mdr1 gene.

New insights into the autotaxin/LPA axis in cancer development and metastasis

“…Ovarian cancer cells expressing high levels of LPA 1 are more resistant to cisplatininduced apoptosis than cells with low levels of this receptor [6]. Recently, Fukui and colleagues showed that exogenous expression of LPA 3 in hepatocarcinoma and breast cancer cells favor cell survival under cisplatin and doxorubicine treatments [41]. The authors further showed that resistance to these drugs was associated with the activation of Mdr1a and Mdr1b genes controling the expression of the ABC transporter [41].…”

“…Recently, Fukui and colleagues showed that exogenous expression of LPA 3 in hepatocarcinoma and breast cancer cells favor cell survival under cisplatin and doxorubicine treatments [41]. The authors further showed that resistance to these drugs was associated with the activation of Mdr1a and Mdr1b genes controling the expression of the ABC transporter [41]. Blocking LPA 1 and LPA 3 in vivo using Ki16425 also prevent and delay the resistance of renal carcinoma cells to the tyrosine kinase inhibitor sunitinib [34].…”

Effect of Phorbol 12-Myristate 13-Acetate on Function and Gene Expression of P-Glycoprotein in Adriamycin-Resistant K562/ADM Cells

“…To avoid or reverse MDR, it is important to know the effect of drugs or compounds on the MDR. Many studies have reported drugs or new compounds with efficient activity to reverse MDR, but a small number of studies have addressed the effect of drugs that can strengthen drug resistance [29,30]. Data on the enhancement of MDR of drugs and the underlying mechanism are still limited.…”