title: SLC25A1, or CIC, is a novel transcriptional target of mutant p53 and a negative tumor prognostic marker.
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.
authors.affiliation: Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC, USA.
authors.forename: Vamsi K
authors.initials: VK
authors.lastname: Kolukula
authors.forename: Geetaram
authors.initials: G
authors.lastname: Sahu
authors.forename: Anton
authors.initials: A
authors.lastname: Wellstein
authors.forename: Olga C
authors.initials: OC
authors.lastname: Rodriguez
authors.forename: Anju
authors.initials: A
authors.lastname: Preet
authors.forename: Vito
authors.initials: V
authors.lastname: Iacobazzi
authors.forename: Gabriella
authors.initials: G
authors.lastname: D'Orazi
authors.forename: Chris
authors.initials: C
authors.lastname: Albanese
authors.forename: Ferdinando
authors.initials: F
authors.lastname: Palmieri
authors.forename: Maria Laura
authors.initials: ML
authors.lastname: Avantaggiati
mesh_terms: D000818:Animals; D027321:Anion Transport Proteins / Q000037:antagonists & inhibitors / Q000235:genetics*; D000970:Antineoplastic Agents / Q000494:pharmacology; D001555:Benzene Derivatives / Q000494:pharmacology; D014408:Biomarkers, Tumor / Q000235:genetics*; D001943:Breast Neoplasms / Q000235:genetics*; D063646:Carcinogenesis / Q000187:drug effects / Q000235:genetics*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects / Q000235:genetics; D002945:Cisplatin / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D005260:Female; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics*; D006801:Humans; D053208:Kaplan-Meier Estimate; D008175:Lung Neoplasms / Q000235:genetics*; D051379:Mice; D024101:Mitochondrial Proteins / Q000037:antagonists & inhibitors / Q000235:genetics*; D009154:Mutation; D027361:Organic Anion Transporters; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000235:genetics*; D011379:Prognosis; D014158:Transcription, Genetic; D014233:Tricarboxylic Acids / Q000494:pharmacology; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism
chemical_list: D027321:Anion Transport Proteins; D000970:Antineoplastic Agents; D001555:Benzene Derivatives; D014408:Biomarkers, Tumor; C085126:FOXO1 protein, human; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; D024101:Mitochondrial Proteins; D027361:Organic Anion Transporters; C532592:Slc25a1 protein, human; D014233:Tricarboxylic Acids; D016159:Tumor Suppressor Protein p53; D002945:Cisplatin