Abstract
A metabolic phenomenon known as the Warburg effect has been characterized in certain cancerous cells, embryonic stem cells, and other rapidly proliferative cell types. Previously, our attempts to induce a Warburg-like state pharmaceutically via CPI-613 and PS48 treatment did augment metabolite production and gene expression; however, this treatment demonstrated a Reverse Warburg effect phenotype observed in cancer-associated stroma. In the current study, we inquired whether the mitochondria were affected by the aforementioned pharmaceutical treatment as observed in cancerous stromal fibroblasts. While the pharmaceutical agents decreased mitochondrial membrane potential in porcine fetal fibroblasts, the number and size of mitochondria were similar, as was the overall cell size. Moreover, the fibroblasts that were treated with CPI-613 and PS48 for a week had increased numbers of large autolysosome vesicles. This coincided with increased intensity of LysoTracker staining in treated cells as observed by flow cytometry. Treated fibroblasts thus may utilize changes in metabolism and autophagy to mitigate the damage of treatment with pharmaceutical agents. These findings shed light on how these pharmaceutical agents interact and how treated cells augment metabolism to sustain viability.
Highlights
A hallmark of the Warburg effect (WE) is predominate use of glycolysis as opposed to use of the tricarboxylic acid (TCA) cycle for energy production
Mitochondrial membrane potential (Δψm) was measured using flow cytometric analysis of JC-10 staining in treated fibroblasts as an estimate of mitochondrial function for respiratory and tricarboxylic acid cycle capacity
We found that treatment with 100 μM CPI yielded the highest proportion (P < 0.01) of fibroblasts with loss of Δψm (95.5% vs. ≤87.3% in lower CPI concentrations; Fig. 1; Table 1)
Summary
A hallmark of the Warburg effect (WE) is predominate use of glycolysis as opposed to use of the tricarboxylic acid (TCA) cycle for energy production. The latter is most commonly used by differentiated cells[1]. We selected the pharmaceutical agents CPI-613 and PS48 in an effort to induce a WE-like metabolism[7]. We found that CPI and PS48 treatment combination did not increase cellular proliferation or decrease cell viability, but did induce changes in expression of genes implicated in cancer metastasis. We inquired how this treatment impacted the mitochondria as some research evidences reduced mitochondrial mass or an absence of detectible mitochondria in cancer stromal cells[6,13]
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