Oncotarget

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SLC25A1, or CIC, is a novel transcriptional target of mutant p53 and a negative tumor prognostic marker.

Vamsi K. Kolukula, Geetaram Sahu, Anton Wellstein, Olga C. Rodriguez, Anju Preet, Vito Iacobazzi, Gabriella D'Orazi, Chris Albanese, Ferdinando Palmieri and Maria Laura Avantaggiati _

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Oncotarget. 2014; 5:1212-1225. https://doi.org/10.18632/oncotarget.1831

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Abstract

Vamsi K. Kolukula1, Geetaram Sahu1, Anton Wellstein1, Olga C. Rodriguez1, Anju Preet1, Vito Iacobazzi2, Gabriella D’Orazi3,4, Chris Albanese1,*, Ferdinando Palmieri2,*, and Maria Laura Avantaggiati1,*.

1 Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC, USA.

2 Department of Biosciences, Biotechnology and Pharmacological Sciences, University of Bari, Italy.

3 Department of Experimental Oncology, Molecular Oncogenesis Laboratory, Regina Elena National Cancer Institute, Rome, Italy.

Department of Medical, Oral and Biotechnological Sciences,  University of Chieti,  66013 Chieti, Italy.

* These authors equally contributed to this manuscript.

Correspondence:

Maria Laura Avantaggiati, email:

Keywords: SLC25A1, CIC, citrate, cancer, p53 mutations, mutant, FOXO-1, survival, prognostic, prognosis, marker.

Received: January 29, 2014 Accepted: March 15, 2014 Published: March 16, 2014

Abstract

Mutations of the p53 gene hallmark many human cancers. Several p53 mutant proteins acquire the capability to promote cancer progression and metastasis, a phenomenon defined as Gain of Oncogenic Function (GOF). The downstream targets by which GOF p53 mutants perturb cellular programs relevant to oncogenesis are only partially known. We have previously demonstrated that SLC25A1 (CIC) promotes tumorigenesis, while its inhibition blunts tumor growth. We now report that CIC is a direct transcriptional target of several p53 mutants. We identify a novel interaction between mutant p53 (mutp53) and the transcription factor FOXO-1 which is responsible for regulation of CIC expression levels. Tumor cells harboring mutp53 display higher CIC levels relative to p53 null or wild-type tumors, and inhibition of CIC activity blunts mutp53-driven tumor growth, partially overcoming GOF activity.  CIC inhibition also enhances the chemotherapeutic potential of platinum-based agents. Finally, we found that elevated CIC levels predict poor survival outcome in tumors hallmarked by high frequency of p53 mutations. Our results identify CIC as a novel target of mutp53 and imply that the employment of CIC inhibitors may improve survival rates and reduce chemo-resistance in tumors harboring these types of mutations, which are among the most intractable forms of cancers.


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