Cooperation of G12/13 and Gi proteins via lysophosphatidic acid receptor-2 (LPA2) signaling enhances cancer cell survival to cisplatin

Kanako Minami; Nanami Ueda; Kaichi Ishimoto; Rio Kurisu; Miyu Takamoto; Hiroko Ikeda; Toshifumi Tsujiuchi

doi:10.1016/j.bbrc.2020.08.087

Cooperation of G12/13 and Gi proteins via lysophosphatidic acid receptor-2 (LPA₂) signaling enhances cancer cell survival to cisplatin

Biochem Biophys Res Commun. 2020 Nov 12;532(3):427-432. doi: 10.1016/j.bbrc.2020.08.087. Epub 2020 Aug 31.

Authors

Kanako Minami¹, Nanami Ueda¹, Kaichi Ishimoto¹, Rio Kurisu¹, Miyu Takamoto¹, Hiroko Ikeda¹, Toshifumi Tsujiuchi²

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.
² Division of Molecular Oncology, Department of Life Science, Faculty of Science and Engineering, Kindai University, 3-4-1, Kowakae, Higashiosaka, Osaka 577-8502, Japan. Electronic address: ttujiuch@life.kindai.ac.jp.

PMID: 32883524
DOI: 10.1016/j.bbrc.2020.08.087

Abstract

Lysophosphatidic acid (LPA) through six subtypes of G protein-coupled LPA receptors (LPA₁ to LPA₆) mediates a variety of cancer cell functions. The aim of this study was to evaluate the cooperative effects of G12/13 and Gi proteins through LPA₂ on cancer cell survival to cisplatin (CDDP). In cell survival assay, cells were treated with CDDP every 24 h for 2 days. The long-term CDDP treated (HT-CDDP) cells established from fibrosarcoma HT1080 cells were pretreated with an LPA₂ agonist, GRI-977143. The cell survival rate to CDDP of HT-CDDP cells was significantly increased by GRI-977143. The elevated cell survival to CDDP was suppressed by LPA₂ knockdown. Since G12/13 protein stimulates Rho-mediated signaling, RhoA and RhoC knockdown cells were generated from HT1080 cells (HT1080-RhoA and HT1080-RhoC cells, respectively). In the presence of GRI-977143, HT1080-RhoA and HT1080-RhoC cells showed the low cell survival rates to CDDP. On the other hand, Gi protein inhibits adenylyl cyclase (AC) activity. Before cell survival assay, cells were treated with a Gi protein inhibitor, pertussis toxin (PTX) for 24 h. The cell survival rate to CDDP of HT1080 cells was significantly reduced by PTX. Furthermore, when HT1080-RhoA and HT1080-RhoC cells were pretreated with PTX, the cell survival rates to CDDP of both cells were markedly inhibited by PTX. The present results suggest that cooperation of G12/13 and Gi proteins activated by LPA₂ enhances the cell survival of HT1080 cells treated with CDDP.

Keywords: Anticancer drug; Cell survival; Fibrosarcoma cells; LPA; LPA(2).

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Antineoplastic Agents / pharmacology
Cell Line, Tumor
Cell Survival / drug effects*
Cell Survival / physiology
Cisplatin / pharmacology*
Fibrosarcoma / drug therapy*
Fibrosarcoma / metabolism
Fibrosarcoma / pathology
GTP-Binding Protein alpha Subunits, G12-G13 / metabolism*
GTP-Binding Protein alpha Subunits, Gi-Go / metabolism*
Gene Expression Regulation, Neoplastic / drug effects
Gene Knockdown Techniques
Humans
Models, Biological
Receptors, Lysophosphatidic Acid / antagonists & inhibitors
Receptors, Lysophosphatidic Acid / genetics
Receptors, Lysophosphatidic Acid / metabolism*
Signal Transduction / drug effects
rhoA GTP-Binding Protein / metabolism
rhoC GTP-Binding Protein / metabolism

Substances

Antineoplastic Agents
LPAR2 protein, human
Receptors, Lysophosphatidic Acid
RHOA protein, human
GTP-Binding Protein alpha Subunits, G12-G13
GTP-Binding Protein alpha Subunits, Gi-Go
RHOC protein, human
rhoA GTP-Binding Protein
rhoC GTP-Binding Protein
Cisplatin