Abstract
Cancer cells are dependent on glutamine for their metabolism and growth. Despite being the most abundant amino acid in the blood, glutamine deprivation occurs in the core of the tumor rendering less access to glutamine to the nearby tumor cells. Tumor cells mostly use the glutamine for mitochondrial oxidative phosphorylation (OXPHOS) to produce energy and the ingredients of the biomass required for the highly proliferating and metastatic ovarian cancer cells. But there is a lack of reports on the regulation of glutamine starvation on metastatic behavior and epithelial to mesenchymal transition (EMT) of ovarian cancer cells. We found that glutamine starvation reduced the migration and invasion properties of the ovarian cancer cells, PA1 and SKOV3. The expression of the invasion-inducing proteins, like matrix metalloproteinases (MMP2 and MMP9), were downregulated upon glutamine starvation. MMP genes are mostly regulated by the ETS1 oncogenic transcription factor in invasive tumor cells. Here we demonstrated the significant involvement of ETS1 on EMT and invasion in glutamine-deprived cells. We have further shown that the regulation of ETS1 expression and nuclear localization upon glutamine starvation is controlled in a cell type-specific manner. In PA1 cells, glutamine-induced ETS1 over-expression is HIF1α-dependent, while in SKOV3, its translocation to the nucleus is regulated through the mTOR pathway. Considering all, our study suggests that glutamine plays a very significant role in migration and invasion in ovarian cancer cells and ETS1 plays a key role in inducing such oncogenic parameters.
Highlights
Invasion and metastasis in cancer cells are the major steps in oncogenesis
For invasion through the basement membrane in a solid tumor, the cells need to digest the extracellular matrix of the surrounding tissue or the secondary tissue site. This is performed by different matrix metalloproteinases (MMPs) secreted by the tumor cells as their activities are enhanced in solid tumors [4]. These MMP (MMP2 and MMP9) genes are transcriptionally regulated by different transcription factors, but most importantly ETS1 has been proposed as a promising factor in this regard especially in epithelial ovarian cancer [5]
The MMP2 protein expression as well as MMP2 and MMP9 in-gel activity was reduced after glutamine starvation (Figure 1H–I, Supplementary Figure 1–3)
Summary
Invasion and metastasis in cancer cells are the major steps in oncogenesis. As cancer progression occurs, the tumor cells move from the primary site to a new secondary site. For invasion through the basement membrane in a solid tumor, the cells need to digest the extracellular matrix of the surrounding tissue or the secondary tissue site. This is performed by different matrix metalloproteinases (MMPs) secreted by the tumor cells as their activities are enhanced in solid tumors [4]. These MMP (MMP2 and MMP9) genes are transcriptionally regulated by different transcription factors, but most importantly ETS1 has been proposed as a promising factor in this regard especially in epithelial ovarian cancer [5]. Vimentin helps directly in cell motility, whereas VEGF overexpression or treatment found to be elicit EMT in cancer cells [6, 7, 8]
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