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Alendronate induces anti-migratory effects and inhibition of neutral phosphatases in UMR106 osteosarcoma cells
M Silvina Molinuevo1, Liliana Bruzzone, Ana M Cortizo
1Bioquímica Patológica, Facultad de Ciencias Exactas, Universidad Nacional de La Plata, 47 y 115 (1900) La Plata, Argentina.
Abstract:
Bisphosphonates are nonhydrolysable pyrophosphate analogues that prevent bone loss in several types of cancer. However, the mechanisms of anticancer action of bisphosphonates are not completely known. We have previously shown that nitrogen-containing bisphosphonates directly inhibit alkaline phosphatase of UMR106 rat osteosarcoma cells. In this study, we evaluated the effects of alendronate on the migration of UMR106 osteosarcoma using a model of multicellular cell spheroids, as well as the alendronate effect on neutral phosphatases. Alendronate significantly inhibited the migration of osteoblasts in a dose-dependent manner (10(-6)-10(-4) M). This effect was also dependent on calcium availability. The spheroid morphology and distribution of actin fibers were also affected by alendronate treatment. Alendronate dose-dependently inhibited neutral phosphatase activity in cell-free osteoblastic extracts as well as in osteoblasts in culture. Our results show that alendronate inhibits cell migration through mechanisms dependent on calcium, and that seem to involve inhibition of phosphotyrosine-neutral-phosphatases and disassembly of actin stress fibers.
Insights
Alendronate, a bisphosphonate, inhibits osteosarcoma cell migration and neutral phosphatase activity. This anticancer effect is calcium-dependent and involves actin fiber disruption.
Area of Science:
- Oncology
- Biochemistry
- Cell Biology
Background:
- Bisphosphonates prevent bone loss in cancer but their anticancer mechanisms are not fully understood.
- Nitrogen-containing bisphosphonates inhibit alkaline phosphatase in UMR106 rat osteosarcoma cells.
Purpose of the Study:
- To evaluate alendronate's effects on UMR106 osteosarcoma cell migration.
- To investigate alendronate's impact on neutral phosphatases and actin cytoskeleton.
Main Methods:
- Utilized a multicellular spheroid model to assess osteosarcoma cell migration.
- Measured neutral phosphatase activity in cell-free extracts and cultured osteoblasts.
- Analyzed spheroid morphology and actin fiber distribution.
Main Results:
- Alendronate significantly inhibited osteosarcoma cell migration in a dose-dependent manner (10⁻⁶–10⁻⁴ M).
- Alendronate's inhibitory effect on migration was calcium-dependent.
- Dose-dependent inhibition of neutral phosphatase activity was observed.
- Alendronate treatment affected spheroid morphology and actin fiber organization, leading to disassembly.
Conclusions:
- Alendronate inhibits osteosarcoma cell migration through calcium-dependent mechanisms.
- These mechanisms appear to involve the inhibition of phosphotyrosine-neutral-phosphatases.
- Alendronate-induced disassembly of actin stress fibers contributes to the observed inhibition of cell migration.
