Lysophosphatidic Acid (LPA) Receptor Signaling Promotes the Adaptation of Malignant Cellular Functions in Highly Migratory Osteosarcoma Cells Under Hypoxic and Low-Glucose Conditions

  • Cell Mol Bioeng. 2025 Oct 13;18(6):577-588. doi: 10.1007/s12195-025-00873-y.
Anri Taniguchi  1 ,  Moemi Tamura  1 ,  Mao Yamamoto  1 ,  Narumi Yashiro  1 ,  Yuka Kusumoto  1 ,  Shion Nagano  1 ,  Nanami Shimomura  1 ,  Miwa Takai  1 ,  Toshifumi Tsujiuchi  1
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.
PMID: 41328303 DOI: 10.1007/s12195-025-00873-y
Abstract

Purpose: In solid tumors, Cancer cells adapt to hypoxic and nutrient deprived environments to support malignant progression. This study examined whether hypoxic and low glucose conditions enhance malignant behaviors more strongly in highly migratory MG63-R10 cells, which are derived from osteosarcoma MG-63 cells, compared to parental MG-63 cells, and further investigated whether lysophosphatidic acid (LPA) receptor signaling regulates this adaptation.

Methods: MG63-R10 and MG-63 cells were cultured under hypoxic (1% O2) or normoxic (21% O2) conditions in media containing 4500, 2000, or 1000 mg/L glucose. LPA receptor expression was analyzed by quantitative real time RT-PCR. Cell growth and motility were assessed, and pharmacological modulators AM966 (LPA1 antagonist), GRI-977143 (LPA2 agonist), and (2S)-OMPT (LPA3 agonist) were used to evaluate receptor specific effects on cell growth and motility.

Results: Under 1% O2, LPAR2 expression increased in MG63-R10 cells, while LPAR1 and LPAR3 expression decreased. MG63-R10 cells showed lower growth than MG-63 cells under 21% O2, but higher growth under hypoxia. MG63-R10 cell motility was higher than that of MG-63 cells at 21% O2 and was further enhanced under 1% O2. AM966 and GRI-977143 increased MG63-R10 motility, whereas (2S)-OMPT suppressed it. MG63-R10 motility significantly increased in 2000 and 1000 mg/L glucose, whereas MG-63 motility remained unchanged across glucose levels.

Conclusion: These results suggest that, compared to parental MG-63 cells, highly migratory osteosarcoma MG63-R10 cells adapt their malignant cellular functions to hypoxic and low-glucose conditions through LPA receptor signaling, highlighting this pathway as a potential therapeutic target in aggressive osteosarcomas.

Supplementary information: The online version contains supplementary material available at 10.1007/s12195-025-00873-y.

Keywords
Cell migration; Hypoxia; LPA receptors; Nutrient deprivation; Osteosarcoma cells.
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