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Contrasting effects of transforming growth factor β1 on programmed cell death of bovine mammary epithelial cell lines
1Department of Biomedical Sciences, Ontario Veterinary College, University of Guelph, 50 Stone Road East, Guelph, ON, N1G 2W1, Canada.
Abstract:
A previous study in the bovine mammary epithelial cell line BME-UV1 demonstrated that suppression of the phosphatidylinositol-4,5-biphosphate 3 kinase (PI3K)/AKT (somatotropic) signaling pathway was required for transforming growth factor β1 (TGFβ1)-induced programmed cell death (PCD). To investigate whether this is a universal mechanism for TGFβ1 to induce PCD in bovine mammary epithelium, we compared TGFβ1 modulation of PI3K/AKT and its role in PCD in 2 bovine mammary epithelial cell lines: MAC-T and BME-UV1. In MAC-T cells, TGFβ1 promoted cell survival, and this paralleled a reduction in PI3K/AKT activity, rather than an increase. In BME-UV1 cells, TGFβ1 induced PCD, and this was accompanied by a time-dependent effect on PI3K/AKT activity, including an initial significant increase in the phosphorylation of AKT at 3 h, followed by a reduction between 12 and 24 h, and then an increase at 48 h. Inhibition of AKT activity enhanced TGFβ1-induced PCD in BME-UV1 cells but had no effect on MAC-T cells, suggesting that TGFβ1 mediates PCD in BME-UV1 cells through suppression of AKT activity. Inhibition of TGFβ receptor type I (TβRI) kinase activity completely abrogated TGFβ1-induced PCD in BME-UV1 cells but had no effect on TGFβ1-induced suppression of PCD in MAC-T cells, demonstrating that TGFβ1-induced PCD in BME-UV1 cells is dependent on TβRI/SMAD signaling. These and previous observations suggest that the different effects of TGFβ1 on PCD in these cell lines might involve noncanonical signaling pathways other than PI3K/AKT, and may reflect their different lineages. Future studies should address this finding, taking into consideration the effect that different culture conditions might have on cell phenotype.
Insights
Transforming growth factor β1 (TGFβ1) induces programmed cell death (PCD) in bovine mammary cells by suppressing phosphatidylinositol-4,5-biphosphate 3 kinase (PI3K)/AKT signaling in BME-UV1 cells, but promotes survival in MAC-T cells.
Area of Science:
- Cell Biology
- Molecular Biology
- Cancer Research
Background:
- Previous studies indicated phosphatidylinositol-4,5-biphosphate 3 kinase (PI3K)/AKT pathway suppression is crucial for transforming growth factor β1 (TGFβ1)-induced programmed cell death (PCD) in bovine mammary epithelial cells.
- The role of TGFβ1 in inducing PCD in bovine mammary epithelium requires further investigation across different cell lines.
Purpose of the Study:
- To compare the effects of TGFβ1 on PI3K/AKT signaling and PCD in two distinct bovine mammary epithelial cell lines: MAC-T and BME-UV1.
- To elucidate the specific signaling pathways involved in TGFβ1-mediated PCD in these cell lines.
Main Methods:
- Investigated TGFβ1 modulation of PI3K/AKT activity and its correlation with PCD in MAC-T and BME-UV1 cells.
- Utilized AKT and TGFβ receptor type I (TβRI) inhibition to assess their roles in TGFβ1-induced PCD.
- Analyzed time-dependent changes in AKT phosphorylation in response to TGFβ1.
Main Results:
- TGFβ1 promoted cell survival in MAC-T cells, associated with reduced PI3K/AKT activity.
- TGFβ1 induced PCD in BME-UV1 cells, with a complex, time-dependent modulation of PI3K/AKT activity.
- Inhibition of AKT enhanced TGFβ1-induced PCD in BME-UV1 cells, while TβRI inhibition abrogated it, confirming TβRI/SMAD signaling dependence.
Conclusions:
- TGFβ1 exhibits differential effects on PCD in bovine mammary epithelial cell lines, suggesting cell-specific mechanisms.
- TGFβ1-induced PCD in BME-UV1 cells is mediated by PI3K/AKT suppression and TβRI/SMAD signaling.
- Noncanonical pathways beyond PI3K/AKT may contribute to TGFβ1's varied roles in mammary epithelial cells, potentially influenced by cell lineage and culture conditions.
