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Lysophosphatidic acid receptor-2 (LPA2)-mediated signaling enhances chemoresistance in melanoma cells treated with anticancer drugs

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Abstract

Lysophosphatidic acid (LPA) signaling through LPA receptors (LPA1 to LPA6) regulates a variety of malignant properties in cancer cells. Recently, we show that LPA2 expression is elevated by long-term cisplatin (CDDP) treatment in melanoma A375 cells. In the present study, we investigated whether LPA2-mediated signaling is involved in the modulation of chemoresistance in A375 cells. In cell survival assay, cells were treated with CDDP and dacarbazine (DTIC) every 24 h for 2 days. The cell survival rates to CDDP and DTIC were markedly increased by an LPA2 agonist, GRI-977143. To validate the effects of LPA2 on cell survival, LPA2 knockdown cells were generated from A375 cells. The cell survival rates elevated by GRI-977143 were suppressed by LPA2 knockdown. To evaluate the roles of LPA2-mediated signaling in cell survival, cells were pretreated with a Gi protein inhibitor, pertussis toxin (PTX). In the presence of GRI-977143, the cell survival rates to CDDP and DTIC were significantly lower in PTX-treated cells than in untreated cells. In addition, pretreatment of an adenylyl cyclase inhibitor, SQ22536, increased the cell survival of A375 cells treated with CDDP and DTIC. These results suggest that LPA2-mediated signaling plays an important role in the enhancement of chemoresistance of A375 cells treated with anticancer drugs.

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Abbreviations

LPA:

Lysophosphatidic acid;

LPA2 :

LPA receptor-2

CDDP:

Cisplatin

DTIC:

Dacarbazine

ABC:

ATP-binding cassette

GST:

Glutathione-S-transferase

RT-PCR:

Reverse transcription-polymerase chain reaction

PTX:

Pertussis toxin

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Acknowledgements

This work was supported by JSPS KAKENHI Grant No. JP18K07249 and by research grants from the Faculty of Science and Engineering, Kindai University.

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Authors and Affiliations

  1. Division of Molecular Oncology, Department of Life Science, Faculty of Science and Engineering, Kindai University, 3-4-1, Kowakae, Higashiosaka, Osaka, 577-8502, Japan

    Kanako Minami, Nanami Ueda, Kaichi Ishimoto & Toshifumi Tsujiuchi

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  1. Kanako Minami
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  2. Nanami Ueda
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  3. Kaichi Ishimoto
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  4. Toshifumi Tsujiuchi
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Correspondence to Toshifumi Tsujiuchi.

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Minami, K., Ueda, N., Ishimoto, K. et al. Lysophosphatidic acid receptor-2 (LPA2)-mediated signaling enhances chemoresistance in melanoma cells treated with anticancer drugs. Mol Cell Biochem 469, 89–95 (2020). https://doi.org/10.1007/s11010-020-03730-w

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