Volume 11, Issue 21 of @Oncotarget reported that as nutrient levels of BCAAs, substrates of BCATc, regulate the PI3K/Akt pathway and the authors hypothesized that increased expression of BCATc would contribute to tumor cell growth through upregulation of the insulin/IGF-1 signaling pathway.
An analysis of this pathway showed that when overexpressed BCATc regulates proliferation through the PI3K/Akt axis, whilst simultaneously attenuating the Ras/Erk pathway indicating that BCATc acts as a conduit between these two pathways.
Dr. Myra Elizabeth Conway Faculty of Health and Applied Sciences, The University of the West of England said, "Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer and is associated with a poor prognosis."
"Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer and is associated with a poor prognosis"
- Dr. Myra Elizabeth Conway, Faculty of Health and Applied Sciences, The University of the West of England
These pathways are controlled through the import of nutrients into cells by growth factors, such as insulin-like growth factor 1, epidermal growth factor, and insulin, which mediate a cascade of events that regulate numerous cellular processes including cell growth and proliferation.
Nutrient status is also sensed by the general control non-derepressible 2 kinase coordinates cell growth, proliferation, and cell survival.
Using the TNBC cell model MDA-MB-231, the authors demonstrate that knockdown of BCATc results in a significant decrease of IGF-1 and insulin-mediated cell proliferation and migration.
Figure 1: Knockdown of BCAT1 significantly reduces proliferation, migration and invasion of MDA-MB-231 cells. Cells were treated with 20 nM BCAT1 siRNA for 72 hours and the effect on proliferation assessed using the tritiated thymidine incorporation assay, migration was assessed using cells seeded onto 8 μm Transwell inserts (Greiner Bio-One) coated with collagen and after 24 hours, migrated were fixed and stained with 0.2% Crystal Violet, solubilised and absorbance measured and to assess invasion Matrigel added to the inserts as described above (A) Respective densitometric analysis of fold changes of protein expression relative to α-tubulin are presented to the right of immunoblots. (B) Fold change in disintegrations per minute (DPM) and representative images of (C) migrated cells and (D) invaded cells with fold changes in absorbance at 590 nm ± SEM presented (n = 3) ***p < 0.001 and ****p < 0.0001 (scale bars = 100 μm).
Subsequent analysis demonstrated that cell proliferation was associated with activation of the PI3K/Akt pathway that resulted in increased activation of FOXO3a, a transcription factor known to be involved in cell proliferation.
Importantly, BCATc at the same time suppressed phosphorylation of ERK, indicating that regulation of proliferation through BCATc is primarily through the PI3K/Akt pathway rather than through ERK signaling, thus highlighting the plasticity of tumors to advance and adapt to changing environments.
The Conway Research Team concluded in their Oncotarget Research Article that BCATc promoted tumor cell survival through evasion of apoptosis mediated potentially through regulation of the redox status of the cells.
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DOI - https://doi.org/10.18632/oncotarget.27607
Full text - https://www.oncotarget.com/article/27607/text/
Correspondence to - Myra Elizabeth Conway - [email protected]
Keywords - BCAT, PI3K/Akt, ERK, breast cancer
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