Tumor cells containing the African-Centric S47 variant of TP53 show increased Warburg metabolism
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Thibaut Barnoud1, Joshua L.D. Parris1,2 and Maureen E. Murphy1
1Program in Molecular and Cellular Oncogenesis, The Wistar Institute, Philadelphia PA 19104, USA
2Cell and Molecular Biology Program, Perelman School of Medicine at the University of Pennsylvania, Philadelphia PA 19104, USA
Maureen E. Murphy, email: [email protected]
Keywords: p53; Pro47Ser; metabolism; RRAD; mitochondria
Received: November 16, 2018 Accepted: January 28, 2019 Published: February 05, 2019
Mutations in the TP53 tumor suppressor gene remain a hallmark of human cancer. In addition to mutation of TP53, single nucleotide polymorphisms (SNPs) in this gene can have a profound impact on p53 function, and can affect cancer risk as well as other p53 functions. Wild type (WT) p53 contains a proline at amino acid 47, but approximately 1% of African-Americans express a p53 allele with a serine at amino acid 47 (Pro47Ser, hereafter S47). In a mouse model for this variant, mice expressing S47 are predisposed to spontaneous cancers. The S47 variant also is associated with increased pre-menopausal breast cancer risk in African American women. 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. In this work, we report on another potentially promising therapeutic vulnerability of S47 tumors. 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. We propose that the altered metabolism in S47 tumor cells may be yet another potentially-actionable therapeutic vulnerability to exploit in cancer-prone individuals with this genotype.
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