Effects of free fatty acid receptor (FFAR) signaling on the modulation of cancer cell functions under hypoxic conditions.

In the tumor environment, hypoxia promotes tumor progression, such as cancer cell growth, migration and chemoresistance. This study aimed to evaluate the roles of free fatty acid receptors (FFARs) in the regulation of cancer cell functions under hypoxic conditions, using fibrosarcoma HT1080 cells. HT1080 cells expressed FFAR1, FFAR2 and FFAR3 genes, but not FFAR4 gene. FFAR1, FFAR2 and FFAR3 expression levels in HT1080 cells cultured at 1 % O2 were elevated, compared with 21 % O2. The cell growth activities of HT1080 cells cultured at 21 % O2 were inhibited by acetic acid (AA) and propanoic acid (PA), but not 1 % O2. HT1080 cell motility was markedly reduced by culturing at 1 % O2. The cell growth and motility of HT1080 cells were enhanced by FFAR2 knockdown. The cell viability to cisplatin (CDDP) of HT1080 cells cultured at 1 % O2 was increased, compared with 21 % O2. FFAR2 knockdown suppressed the cell viability to CDDP of HT1080 cells. On the other hand, the cell motility and viability to CDDP of HT1080 cells cultured at 21 % O2 were suppressed by TUG-770. When HT1080 cells were cultured at 1 % O2, the cell motility and viability to CDDP were decreased, correlating with FFAR1 expression level. Moreover, FFAR1 knockdown increased the cell viability to CDDP of HT1080 cells cultured at 1 % O2. These results suggest that FFAR-mediated signaling plays an important role in the modulation of cellular functions of HT1080 cells under hypoxic conditions.

Roles of lysophosphatidic acid (LPA) receptor-mediated signaling in cellular functions modulated by endothelial cells in pancreatic cancer cells under hypoxic conditions.

BACKGROUND: In the tumor environment, malignant characteristics of cancer cells are promoted by stromal cells under hypoxia. It is unknown whether lysophosphatidic acid (LPA) receptor-mediated signaling is involved in the regulation of cellular functions by endothelial cells in pancreatic cancer cells under hypoxic conditions. METHODS: Pancreatic cancer (PANC-1) cells were co-cultured with endothelial (F2) cells and F2 cell supernatants at 21% and 1% O2. The Cell Culture Insert was used to assess the cell motile activity. The cell growth and viability to cisplatin (CDDP) were measured, using the Cell Counting Kit-8. RESULTS: LPA receptor expression levels were changed in PANC-1 cells co-cultured with F2 cells at 21% and 1% O2. The cell motile activities of PANC-1 cells co-cultured with F2 cells at 21% and 1% O2 were markedly elevated, compared with PANC-1 cells alone. The cell viabilities to CDDP of PANC-1 cells co-cultured with F2 cell supernatants at 21% and 1% O2 were regulated by the activation of LPA receptors. CONCLUSION: These results suggest that LPA receptor-mediated signaling plays an important role in the modulation of pancreatic cancer cell functions by endothelial cells under hypoxic conditions.

Regulation of cellular responses to X-ray irradiation through the activation of lysophosphatidic acid (LPA) receptor-3 (LPA3) and LPA2 in osteosarcoma cells.

Lysophosphatidic acid (LPA) binds to its specific G protein-coupled LPA receptors (LPA1 to LPA6), resulting in the activation of various cellular functions. LPA receptor-mediated signaling facilitates tumor progression in human malignancies. In the present study, we investigated whether LPA receptor-mediated signaling contributes to cellular responses to X-ray irradiation in osteosarcoma MG-63 cells. After X-ray irradiation (2, 4 and 8 Gy), LPAR2 and LPAR3 expression levels in MG-63 cells were significantly elevated in a dose-dependent manner, but no change of LPAR1 expression level was observed. The cell growth activities of MG-63 cells irradiated with X-rays (2, 4 and 8 Gy) were reduced by LPA. Conversely, LPA3 agonist (2 S)-OMPT enhanced the cell growth activities of X-ray irradiated MG-63 cells. The cell movement of MG-63 cells exposed to X-ray irradiation (8 Gy) was inhibited by (2 S)OMPT. In cell survival assay, (2 S)-OMPT suppressed the cell survival to cisplatin (CDDP) of MG-63 cells irradiated with X-rays (8 Gy). The cell survival to CDDP of X-ray irradiated cells was elevated by LPA3 knockdown. Moreover, we evaluated the effects of LPA2 on the cell survival to CDDP of MG-63 cells exposed to X-ray irradiation (8 Gy). The cell survival to CDDP of X-ray irradiated cells was increased by LPA2 agonist GRI-977143 and reduced by LPA2 knockdown. These results suggest that LPA receptor-signaling participates in the modulation of cellular functions induced by X-ray irradiation in osteosarcoma cells.