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Tumor cells containing the African-Centric S47 variant of TP53 show increased Warburg metabolism


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The cover for issue 11 of Oncotarget features Figure 3, "Tumor cells with the S47 variant of p53 show increased sensitivity to 2-Deoxy-D-glucose (2-DG)," by Barnoud, et al.

We recently reported that S47 tumor cells are resistant to the majority of cytotoxic chemotherapeutic agents, but show increased sensitivity to a subset of anti-cancer agents, compared to tumors with WT p53.

We find that S47 tumors show decreased mitochondrial metabolism, along with increased dependency on glycolysis.

S47 tumor cells also show increased sensitivity to the glycolytic poison 2-deoxy-glucose.

"The TP53 tumor suppressor plays a critical role in suppressing tumorigenesis by directly regulating the expression of genes that promote apoptosis, cell cycle arrest, and senescence."

Figure 3: Tumor cells with the S47 variant of p53 show increased sensitivity to 2-Deoxy-D-glucose (2-DG). (A) IC50 analysis using Alamar Blue assays in WT and S47 E1A/RAS tumor cells treated with 2-DG (left panel) or the pentose phosphate pathway inhibitor 6-aminonicotinamide (6-AN, right panel). (B) WT and S47 E1A/RAS MEFs were plated at a density of 10,000 cells per well in 24-well plates. The next day, cells were treated with the indicated concentrations of 2-DG for 48 hours. Cells were then fixed with 10% formalin and stained with 0.5% Crystal Violet. Shown are representative images of duplicate wells from experiments performed in triplicate, which were repeated twice. (C) Quantitation of (B) as per absorbance at 590 nm. **p < 0.01, ***p < 0.001. (D) 700,000 WT and S47 E1A/RAS MEFs were plated in 100-mm dishes. The next day, cell were treated with the indicated doses of 2-DG for 24 hours. Cell lysates were subjected to Western blot analysis, and immunoblotted for p53, cleaved caspase-3 (CC3), p21, and GAPDH (loading control).

Cancer stem cells, also called tumor-initiating cells, drive tumorigenesis and tumor heterogeneity through their abilities to self-renew and generate tumorigenic progeny.

For instance, TAZ confers self-renewal capacity, a CSC property, on breast, brain, and oral cancer cells, probably by inducing the EMT.

Similarly, YAP confers some CSC properties, such as sphere formation and chemoresistance, on hepatocellular carcinoma, esophageal cancer, osteosarcoma, and basal-like breast cancer cells by coordinating the expression of interleukin 6 and stemness marker proteins such as SOX2, SOX9, and CD90.

Nevertheless, the biological roles of LATS1/2, as well as the mechanisms by which they enable cancer cells to acquire and maintain CSC properties, are incompletely understood.

In this study, using SAS cells as a model of CSCs in OSCC, we showed that LATS1/2 are essential for self-renewal of CSCs, and in particular for the initiation of sphere formation.

"In addition to mutations, there are single nucleotide polymorphisms in TP53 that dampen p53 function, and that can increase cancer risk and decrease the efficacy of cancer therapy."

Full text - https://doi.org/10.18632/oncotarget.26660

Correspondence to - Maureen E. Murphy - mmurphy@wistar.org

Keywords - p53, Pro47Ser, metabolism, RRAD, mitochondria



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