Distinct roles of lysophosphatidic acid (LPA) receptor signaling in regulating gastric cancer cell functions under chemical versus physiological hypoxia

Article

作者: Yamamoto, Mao ; Yashiro, Narumi ; Tsujiuchi, Toshifumi ; Shimomura, Nanami ; Kusumoto, Yuka ; Tamura, Moemi ; Takai, Miwa ; Nagano, Shion

Hypoxia plays a crucial role in driving tumor progression by altering cellular signaling pathways. Lysophosphatidic acid (LPA) receptor signaling regulates malignant properties in cancer cells, including motility and chemoresistance. This study aimed to compare the cellular functions of gastric cancer AGS cells under cobalt chloride (CoCl₂)-induced hypoxia and true hypoxia (1 % O₂), with a focus on the role of LPA receptor signaling in mediating these responses. Treatment with CoCl₂ (200 μM) elevated LPAR1 and LPAR3 expression while reducing LPAR2 expression, resulting in enhanced cell motility. CoCl₂ also increased AGS cell viability in response to cisplatin (CDDP) in the presence of LPA. These effects were suppressed by LW6, an inhibitor of HIF-1α, indicating HIF-1α involvement. Furthermore, AGS cel motility and CDDP resistance were enhanced by AM966 (LPA₁ antagonist), GRI-977143 (LPA₂ agonist), and (2S)-OMPT (LPA₃ agonist), suggesting that LPA₂ and LPA₃ promote, while LPA₁ suppresses, these cellular functions under CoCl₂-induced hypoxia. In contrast, under 1 % O₂ conditions, LPAR1 and LPAR3 expression levels were downregulated, while LPAR2 expression remained unchanged. AGS cells cultured at 1 % O₂ showed increased motility but reduced viability in response to CDDP. LW6 further inhibited viability under these conditions. Our results demonstrate that LPA receptor signaling is differentially regulated under CoCl₂-induced and true hypoxia, contributing to distinct outcomes in cell motility and drug response. This suggests that LPA receptor signaling is a potential target for controlling hypoxia-induced malignant transformation in gastric cancer cells.

2025-12-01·Cellular and Molecular Bioengineering

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

Article

作者: Yamamoto, Mao ; Takai, Miwa ; Yashiro, Narumi ; Taniguchi, Anri ; Tamura, Moemi ; Nagano, Shion ; Tsujiuchi, Toshifumi ; Shimomura, Nanami ; Kusumoto, Yuka

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.

2025-09-01·ACTA HISTOCHEMICA

Lysophosphatidic acid (LPA) receptor signaling enhances malignant potential in highly migratory lung cancer cells under hypoxic conditions

Article

作者: Yamamoto, Mao ; Yashiro, Narumi ; Taniguchi, Anri ; Tamura, Moemi ; Shimomura, Nanami ; Takai, Miwa ; Tsujiuchi, Toshifumi ; Nagano, Shion ; Kusumoto, Yuka

Hypoxia contributes to tumor progression, promoting cancer cell motility, invasion and metastasis. Lysophosphatidic acid (LPA) receptors are implicated in the pathogenesis of cancer. In this study, we investigated the role of LPA receptor signaling in modulating malignant behavior under hypoxic conditions (1 % O₂) in lung cancer cells. We generated highly migratory A549-R12 cells from the parental lung cancer A549 cells for this purpose. LPAR1 and LPAR2 expression levels were lower in both A549 and A549-R12 cells cultured at 1 % O₂ compared to those cultured at 21 % O₂, while LPAR3 expression remained unchanged between the two cell lines. Cell motility increased in both A549 and A549-R12 cells cultured at 1 % O₂. Notably, A549-R12 cells exhibited greater motility under 1 % O₂ conditions than A549 cells. Treatment with AM966 (an LPA₁ antagonist) and (2S)-OMPT (an LPA₃ agonist) further increased the motility of A549-R12 cells, while GRI-977143 (an LPA₂ agonist) decreased their motility. Moreover, the invasion activity of A549-R12 cells was higher than that of A549 cells, with 1 % O₂ conditions significantly enhancing A549-R12 cell invasion. AM966 and (2S)-OMPT stimulated, whereas GRI-977143 inhibited, the invasion of A549-R12 cells. In the presence of LPA, cell viability to cisplatin (CDDP) was higher in A549-R12 cells cultured at both 21 % and 1 % O₂ compared to A549 cells. These results suggest that LPA receptor signaling plays a key role in regulating malignant progression in highly migratory lung cancer cells under hypoxic conditions.

100 项与 AM966 相关的药物交易

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