Abstract 66: Corruption of the activity of the mitochondria citrate transporter, CIC, by mutant forms of p53

• Published in: Cancer research (Chicago, Ill.) Vol. 70; no. 8_Supplement; p. 66
• Main Authors: Sahu, Geetaram, Rodriguez, Olga Catalina, Kolukula, Vamsi, Catania, Jason, Preet, Anju, Arshed, Arslaan, Albanese, Christopher, Avantaggiati, Maria L.
• Format: Journal Article
• Language: English
• Published: 15-04-2010
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/1538-7445.AM10-66

Introduction. A distinctive feature of cancer cells is the implementation of the synthesis of fatty acids (FA), (lipogenesis), which is instead suppressed in most normal adult tissues. Because metabolites produced via lipogenesis provide redox potential and influence the activity of enzymes involved in transcription regulation, by turning on this pathway tumor cells might enable metabolic and transcriptional adjustments necessary for survival in various stress conditions. A still unanswered question is whether oncogenes expressed in human tumors directly favor the shift towards lipogenesis and, if so, whether this has consequences for proliferation or for therapy. The initial goal of this study was to identify metabolic gene targets regulated by tumor-derived mutant forms of the p53 gene product, whose role in metabolism is currently unknown.
Results. We found that p53 mutants enhance the expression levels of the mitochondria citrate transporter, CIC. CIC is central to lipogenesis as it scaffolds citrate from the mitochondria to the cytosol, yielding acetyl-CoA, in turn necessary for fatty acid synthesis. Data extracted from gene expression databases, confirmed a strong association between high levels of CIC mRNA and p53 mutant-expressing human tumors, suggesting that up-regulation of CIC is a molecular signature for p53 mutations. CIC up-regulation is also a negative prognostic factor, and a predictor of tumor recurrence, thus mirroring the negative prognostic value of p53 mutant positive tumors. We show that the CIC promoter is transcriptionally up-regulated by mutant p53, via a unique mechanism that involves p53 mutant binding to FOXO-1- and to p53-consensus elements contained therein, as well as a physical interaction between these two proteins. Importantly, while in glucose-deprived cells CIC promoter activity is physiologically shut down, p53 mutants maintain higher levels of CIC transcription in these conditions. This is in contrast with wild-type p53 that suppresses CIC transcription. Furthermore, we demonstrate that inhibition of CIC with a siRNA, or blocking export of citrate to the cytoplasm with a CIC inhibitor, lowers fatty acid levels and impairs survival of p53-mutant tumors. This effect is not seen in pseudo-normal or tumor cells that have a wild-type p53 gene, again suggesting specificity for mutant p53. Additional experiments indicate that by promoting cytoplasmic export of citrate, elevated CIC levels might hamper mitochondrial pathways of energy production.
Conclusions. We have identified the first metabolic signature gene regulated by p53 mutants, CIC, and shown that some tumors expressing these proteins depend upon CIC up-regulation and FA synthesis for survival especially in metabolic stress conditions. Furthermore, we have identified strategies for targeting CIC activity, thus opening new opportunities for the treatment of p53 positive tumors.
Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 66.