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Ganglioside GD1a suppression of NOS2 expression via ERK1 pathway in mouse osteosarcoma FBJ cells
Ting Cao1, Tianyi Zhang, Li Wang
1Laboratory of Tumor Biology and Glycobiology, Department of Life Sciences, Shenyang Pharmaceutical University, Shenyang 110016, People's Republic of China.
Abstract:
Inducible nitric oxide synthase (NOS2) is over-expressed in a number of tumors and implicated in tumor growth and metastasis. Murine FBJ osteosarcoma-derived FBJ-S1 cells are poorly metastatic and express the ganglioside GD1a, whereas highly metastatic FBJ-LL cells only slightly express this ganglioside. The present study demonstrates that NOS2 is more highly expressed in FBJ-LL cells compared to FBJ-S1 cells. By manipulating GM2/GD2 synthase expression or adding exogenous GD1a, GD1a inversely regulated NOS2 at the transcriptional level. GT1b suppressed NOS2 to the same extent as GD1a. Silencing NOS2 inhibited proliferation, migration, and anchorage-independent growth of FBJ-LL cells, suggesting that the metastatic properties of FBJ-LL cells are associated with NOS2. MEK1/2 inhibitor (U0126) increased NOS2 expression, whereas GD1a treatment decreased it. Co-treating the cells with GD1a and U0126 blocked the inhibition of NOS2 expression, suggesting that the GD1a signal is mediated by ERK1/2. NOS2 expression increased when ERK1, but not ERK2, was silenced, and GD1a did not suppress NOS2 expression in cells treated with another MEK1/2 inhibitor PD98059, suggesting that ERK1 phosphorylation is indispensable for the GD1a signal suppressing NOS2.
Insights
Inducible nitric oxide synthase (NOS2) is overexpressed in tumors and linked to metastasis. Ganglioside GD1a suppresses NOS2 expression via ERK1 signaling, inhibiting tumor cell growth and migration.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Inducible nitric oxide synthase (NOS2) is overexpressed in various tumors, contributing to tumor growth and metastasis.
- Gangliosides, like GD1a, play roles in cell signaling and cancer progression.
- FBJ osteosarcoma cell lines (FBJ-S1 and FBJ-LL) exhibit differential metastatic potential and GD1a expression.
Purpose of the Study:
- To investigate the relationship between NOS2 expression, ganglioside GD1a, and the metastatic properties of FBJ osteosarcoma cells.
- To elucidate the signaling pathway through which GD1a regulates NOS2 expression.
Main Methods:
- Comparative analysis of NOS2 expression in FBJ-S1 and FBJ-LL cells.
- Manipulation of GM2/GD2 synthase expression and addition of exogenous GD1a.
- Silencing of NOS2 and specific ERK pathway components (ERK1, ERK2).
- Treatment with MEK1/2 inhibitors (U0126, PD98059).
Main Results:
- Highly metastatic FBJ-LL cells showed higher NOS2 expression than poorly metastatic FBJ-S1 cells.
- GD1a and GT1b inversely regulated NOS2 transcriptionally; GD1a suppressed NOS2.
- Silencing NOS2 reduced FBJ-LL cell proliferation, migration, and anchorage-independent growth.
- GD1a's suppression of NOS2 was mediated by ERK1/2 signaling, specifically involving ERK1 phosphorylation.
Conclusions:
- NOS2 expression is associated with the metastatic potential of FBJ osteosarcoma cells.
- Ganglioside GD1a suppresses NOS2 expression through an ERK1-dependent pathway.
- Targeting NOS2 or modulating GD1a signaling may represent therapeutic strategies for osteosarcoma metastasis.
