Loss of the mitochondrial citrate carrier, Slc25a1/CIC disrupts embryogenesis via 2-Hydroxyglutarate.

Biallelic germline mutations in the SLC25A1 gene lead to combined D/L-2-hydroxyglutaric aciduria (D/L-2HGA), a fatal systemic disease uniquely characterized by the accumulation of both enantiomers of 2-hydroxyglutaric acid (2HG). How SLC25A1 deficiency contributes to D/L-2HGA and the role played by 2HG is unclear and no therapy exists. Both enantiomers act as oncometabolites, but their activities in normal tissues remain understudied. Here we show that mice lacking both SLC25A1 alleles exhibit developmental abnormalities that mirror human D/L-2HGA. SLC25A1 deficient cells undergo premature senescence, suggesting that loss of proliferative capacity underlies the pathogenesis of D/L-2HGA. Remarkably, D- and L-2HG directly induce senescence and treatment of zebrafish embryos with the combination of D- and L-2HG phenocopies SLC25A1 loss, leading to developmental abnormalities in an additive fashion relative to either enantiomer alone. Metabolic analyses further demonstrate that cells with dysfunctional SLC25A1 undergo mitochondrial respiratory deficit and remodeling of the metabolism and we propose several strategies to correct these defects. These results reveal for the first time pathogenic and growth suppressive activities of 2HG in the context of SLC25A1 deficiency and suggest that targeting the 2HG pathway may be beneficial for the treatment of D/L-2HGA.

Provocative non-canonical roles of p53 and AKT signaling: A role for Thymosin ß4 in medulloblastoma.

The PI3K/AKT and p53 pathways are key regulators of cancer cell survival and death, respectively. Contrary to their generally accepted roles, several lines of evidence, including ours in medulloblastoma, the most common childhood brain cancer, highlight non-canonical functions for both proteins and show a complex context-dependent dynamic behavior in determining cell fate. Interestingly, p53-mediated cell survival and AKT-mediated cell death can dominate in certain conditions, and these interchangeable physiological functions may potentially be manipulated for better clinical outcomes. This review article presents studies in which p53 and AKT behave contrary to their well-established functions. We discuss the factors and circumstances that may be involved in mediating these changes and the implications of these unique roles of p53 and AKT in devising therapeutic strategies. Lastly, based on our recent finding of Thymosin beta 4-mediated chemosensitivity via an AKT-p53 interaction in medulloblastoma cells, we also discuss the possible implications of Thymosin beta-4 in enhancing drug sensitivity in this deadly childhood disease.

Arginase Pathway Markers of Immune-Microenvironment in Thymic Epithelial Tumors and Small Cell Lung Cancer.

BACKGROUND: Key regulators of antitumor immunity such as arginase-1 and the adenosine pathway may have an important role in modulating the effect of immunotherapy. Here, we investigated the expression profile of these immune-related biomarkers in thymic epithelial tumors (TETs) and small cell lung cancer (SCLC), 2 solid tumors where immune checkpoint inhibitors have activity. MATERIALS AND METHODS: Immunohistochemical staining was performed using tissue microarrays of 123 TET (110 thymoma and 13 thymic carcinoma) and 125 SCLC cases. The expression profile of the following immune-related biomarkers was assessed: arginase-1, CD39, CD73, A2AR, PD-L2, and CD15. The expression profile was also correlated with clinical data. RESULTS: No sample was positive for arginase-1. In the adenosine pathway, the prevalence of positive staining for CD39, CD73, and A2AR was 4.9%, 2.5%, and 69.2%, in TETs and 0%, 1.7%, and 50.8%, in SCLC. The multivariate analysis showed that CD39 expression was significantly associated with worse disease related survival (hazard ratio [HR], 10.36; 95% confidence interval [CI]: 2.01-53.47; P= .005) and a shorter time-to progression (HR, 11.35; 95% CI, 2.11-61.23; P = .005) in TETs. Other biomarkers were not associated with disease related survival or time to progression in TETs. No biomarker was associated with survival in SCLC. CONCLUSION: Arginase-1 was not detectable in TETs and SCLC. Expression of markers in the adenosine pathway were present in both TETs and SCLC. CD39 expression in tumor cells may identify subsets of patients with TETs with an unfavorable prognosis.

Regulation of Chemosensitivity in Human Medulloblastoma Cells by p53 and the PI3 Kinase Signaling Pathway.

In medulloblastoma, p53 expression has been associated with chemoresistance and radiation resistance and with poor long-term outcomes in the p53-mutated sonic hedgehog, MYC-p53, and p53-positive medulloblastoma subgroups. We previously established a direct role for p53 in supporting drug resistance in medulloblastoma cells with high basal protein expression levels (D556 and DAOY). We now show that p53 genetic suppression in medulloblastoma cells with low basal p53 protein expression levels (D283 and UW228) significantly reduced drug responsiveness, suggesting opposing roles for low p53 protein expression levels. Mechanistically, the enhanced cell death by p53 knockdown in high-p53 cells was associated with an induction of mTOR/PI3K signaling. Both mTOR inhibition and p110α/PIK3CA induction confirmed these findings, which abrogated or accentuated the enhanced chemosensitivity response in D556 cells respectively while converse was seen in D283 cells. Co-treatment with G-actin-sequestering peptide, thymosin ß4 (Tß4), induced p-AKTS473 in both p53-high and p53-low cells, enhancing chemosensitivity in D556 cells while enhancing chemoresistance in D283 and UW228 cells. IMPLICATIONS: Collectively, we identified an unexpected role for the PI3K signaling in enhancing cell death in medulloblastoma cells with high basal p53 expression. These studies indicate that levels of p53 immunopositivity may serve as a diagnostic marker of chemotherapy resistance and for defining therapeutic targeting.

The Mitochondrial Citrate Carrier SLC25A1/CIC and the Fundamental Role of Citrate in Cancer, Inflammation and Beyond.

The mitochondrial citrate/isocitrate carrier, CIC, has been shown to play an important role in a growing list of human diseases. CIC belongs to a large family of nuclear-encoded mitochondrial transporters that serve the fundamental function of allowing the transit of ions and metabolites through the impermeable mitochondrial membrane. Citrate is central to mitochondrial metabolism and respiration and plays fundamental activities in the cytosol, serving as a metabolic substrate, an allosteric enzymatic regulator and, as the source of Acetyl-Coenzyme A, also as an epigenetic modifier. In this review, we highlight the complexity of the mechanisms of action of this transporter, describing its involvement in human diseases and the therapeutic opportunities for targeting its activity in several pathological conditions.

Predicting new drug indications for prostate cancer: The integration of an in silico proteochemometric network pharmacology platform with patient-derived primary prostate cells.

BACKGROUND: Drug repurposing enables the discovery of potential cancer treatments using publically available data from over 4000 published Food and Drug Administration approved and experimental drugs. However, the ability to effectively evaluate the drug's efficacy remains a challenge. Impediments to broad applicability include inaccuracies in many of the computational drug-target algorithms and a lack of clinically relevant biologic modeling systems to validate the computational data for subsequent translation. METHODS: We have integrated our computational proteochemometric systems network pharmacology platform, DrugGenEx-Net, with primary, continuous cultures of conditionally reprogrammed (CR) normal and prostate cancer (PCa) cells derived from treatment-naive patients with primary PCa. RESULTS: Using the transcriptomic data from two matched pairs of benign and tumor-derived CR cells, we constructed drug networks to describe the biological perturbation associated with each prostate cell subtype at multiple levels of biological action. We prioritized the drugs by analyzing these networks for statistical coincidence with the drug action networks originating from known and predicted drug-protein targets. Prioritized drugs shared between the two patients' PCa cells included carfilzomib (CFZ), bortezomib (BTZ), sulforaphane, and phenethyl isothiocyanate. The effects of these compounds were then tested in the CR cells, in vitro. We observed that the IC50 values of the normal PCa CR cells for CFZ and BTZ were higher than their matched tumor CR cells. Transcriptomic analysis of CFZ-treated CR cells revealed that genes involved in cell proliferation, proteases, and downstream targets of serine proteases were inhibited while KLK7 and KLK8 were induced in the tumor-derived CR cells. CONCLUSIONS: Given that the drugs in the database are extremely well-characterized and that the patient-derived cells are easily scalable for high throughput drug screening, this combined in vitro and in silico approach may significantly advance personalized PCa treatment and for other cancer applications.

Mutant GTF2I induces cell transformation and metabolic alterations in thymic epithelial cells.

The pathogenesis of thymic epithelial tumors (TETs) is poorly understood. Recently we reported the frequent occurrence of a missense mutation in the GTF2I gene in TETs and hypothesized that GTF2I mutation might contribute to thymic tumorigenesis. Expression of mutant TFII-I altered the transcriptome of normal thymic epithelial cells and upregulated several oncogenic genes. Gtf2i L424H knockin cells exhibited cell transformation, aneuploidy, and increase tumor growth and survival under glucose deprivation or DNA damage. Gtf2i mutation also increased the expression of several glycolytic enzymes, cyclooxygenase-2, and caused modifications of lipid metabolism. Elevated cyclooxygenase-2 expression by Gtf2i mutation was required for survival under metabolic stress and cellular transformation of thymic epithelial cells. Our findings identify GTF2I mutation as a new oncogenic driver that is responsible for transformation of thymic epithelial cells.

Inhibition of the mitochondrial citrate carrier, Slc25a1, reverts steatosis, glucose intolerance, and inflammation in preclinical models of NAFLD/NASH.

Nonalcoholic fatty liver disease (NAFLD) and its evolution to inflammatory steatohepatitis (NASH) are the most common causes of chronic liver damage and transplantation that are reaching epidemic proportions due to the upraising incidence of metabolic syndrome, obesity, and diabetes. Currently, there is no approved treatment for NASH. The mitochondrial citrate carrier, Slc25a1, has been proposed to play an important role in lipid metabolism, suggesting a potential role for this protein in the pathogenesis of this disease. Here, we show that Slc25a1 inhibition with a specific inhibitor compound, CTPI-2, halts salient alterations of NASH reverting steatosis, preventing the evolution to steatohepatitis, reducing inflammatory macrophage infiltration in the liver and adipose tissue, while starkly mitigating obesity induced by a high-fat diet. These effects are differentially recapitulated by a global ablation of one copy of the Slc25a1 gene or by a liver-targeted Slc25a1 knockout, which unravel dose-dependent and tissue-specific functions of this protein. Mechanistically, through citrate-dependent activities, Slc25a1 inhibition rewires the lipogenic program, blunts signaling from peroxisome proliferator-activated receptor gamma, a key regulator of glucose and lipid metabolism, and inhibits the expression of gluconeogenic genes. The combination of these activities leads not only to inhibition of lipid anabolic processes, but also to a normalization of hyperglycemia and glucose intolerance as well. In summary, our data show for the first time that Slc25a1 serves as an important player in the pathogenesis of fatty liver disease and thus, provides a potentially exploitable and novel therapeutic target.

The Sustained Induction of c-MYC Drives Nab-Paclitaxel Resistance in Primary Pancreatic Ductal Carcinoma Cells.

Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive disease with limited and, very often, ineffective medical and surgical therapeutic options. The treatment of patients with advanced unresectable PDAC is restricted to systemic chemotherapy, a therapeutic intervention to which most eventually develop resistance. Recently, nab-paclitaxel (n-PTX) has been added to the arsenal of first-line therapies, and the combination of gemcitabine and n-PTX has modestly prolonged median overall survival. However, patients almost invariably succumb to the disease, and little is known about the mechanisms underlying n-PTX resistance. Using the conditionally reprogrammed (CR) cell approach, we established and verified continuously growing cell cultures from treatment-naïve patients with PDAC. To study the mechanisms of primary drug resistance, nab-paclitaxel-resistant (n-PTX-R) cells were generated from primary cultures and drug resistance was verified in vivo, both in zebrafish and in athymic nude mouse xenograft models. Molecular analyses identified the sustained induction of c-MYC in the n-PTX-R cells. Depletion of c-MYC restored n-PTX sensitivity, as did treatment with either the MEK inhibitor, trametinib, or a small-molecule activator of protein phosphatase 2a. IMPLICATIONS: The strategies we have devised, including the patient-derived primary cells and the unique, drug-resistant isogenic cells, are rapid and easily applied in vitro and in vivo platforms to better understand the mechanisms of drug resistance and for defining effective therapeutic options on a patient by patient basis.

YAP/TAZ Inhibition Induces Metabolic and Signaling Rewiring Resulting in Targetable Vulnerabilities in NF2-Deficient Tumor Cells.

Merlin/NF2 is a bona fide tumor suppressor whose mutations underlie inherited tumor syndrome neurofibromatosis type 2 (NF2), as well as various sporadic cancers including kidney cancer. Multiple Merlin/NF2 effector pathways including the Hippo-YAP/TAZ pathway have been identified. However, the molecular mechanisms underpinning the growth and survival of NF2-mutant tumors remain poorly understood. Using an inducible orthotopic kidney tumor model, we demonstrate that YAP/TAZ silencing is sufficient to induce regression of pre-established NF2-deficient tumors. Mechanistically, YAP/TAZ depletion diminishes glycolysis-dependent growth and increases mitochondrial respiration and reactive oxygen species (ROS) buildup, resulting in oxidative-stress-induced cell death when challenged by nutrient stress. Furthermore, we identify lysosome-mediated cAMP-PKA/EPAC-dependent activation of RAF-MEK-ERK signaling as a resistance mechanism to YAP/TAZ inhibition. Finally, unbiased analysis of TCGA primary kidney tumor transcriptomes confirms a positive correlation of a YAP/TAZ signature with glycolysis and inverse correlations with oxidative phosphorylation and lysosomal gene expression, supporting the clinical relevance of our findings.

The mitochondrial citrate carrier, SLC25A1, drives stemness and therapy resistance in non-small cell lung cancer.

Therapy resistance represents a clinical challenge for advanced non-small cell lung cancer (NSCLC), which still remains an incurable disease. There is growing evidence that cancer-initiating or cancer stem cells (CSCs) provide a reservoir of slow-growing dormant populations of cells with tumor-initiating and unlimited self-renewal ability that are left behind by conventional therapies reigniting post-therapy relapse and metastatic dissemination. The metabolic pathways required for the expansion of CSCs are incompletely defined, but their understanding will likely open new therapeutic opportunities. We show here that lung CSCs rely upon oxidative phosphorylation for energy production and survival through the activity of the mitochondrial citrate transporter, SLC25A1. We demonstrate that SLC25A1 plays a key role in maintaining the mitochondrial pool of citrate and redox balance in CSCs, whereas its inhibition leads to reactive oxygen species build-up thereby inhibiting the self-renewal capability of CSCs. Moreover, in different patient-derived tumors, resistance to cisplatin or to epidermal growth factor receptor (EGFR) inhibitor treatment is acquired through SLC25A1-mediated implementation of mitochondrial activity and induction of a stemness phenotype. Hence, a newly identified specific SLC25A1 inhibitor is synthetic lethal with cisplatin or with EGFR inhibitor co-treatment and restores antitumor responses to these agents in vitro and in animal models. These data have potential clinical implications in that they unravel a metabolic vulnerability of drug-resistant lung CSCs, identify a novel SLC25A1 inhibitor and, lastly, provide the first line of evidence that drugs, which block SLC25A1 activity, when employed in combination with selected conventional antitumor agents, lead to a therapeutic benefit.

Characterization of the effects of defined, multidimensional culture conditions on conditionally reprogrammed primary human prostate cells.

The inability to propagate human prostate epithelial cells indefinitely has historically presented a serious impediment to prostate cancer research. The conditionally reprogrammed cell (CRC) approach uses the combination of irradiated J2 mouse fibroblasts and a Rho kinase inhibitor such as Y27632 to support the continuous culture of cells derived from most epithelial tissues, including the prostate. Due to their rapid establishment and overall ease of use, CRCs are now widely used in a variety of basic and preclinical settings. In addition, CRCs were successfully used to clinically treat respiratory papillomatosis. Although both normal and tumor-derived prostate CRCs have been used to study the basic biology of prostate cancer and to test new therapies, certain limitations exist. We have previously reported that prostate CRCs form functional prostate glands when implanted under the mouse renal capsule. However in conventional culture, the prostate CRCs exist in an adult stem-like, transient amplifying state and consequently do not adequately recapitulate several important features of a differentiated prostate epithelium. To address these limitations, we previously described a transwell dish-based model that supported the culturing of prostate CRCs and the collection of cells and cell extracts for molecular and genetic analyses. Using normal and tumor-derived prostate CRCs, we describe the combined effects of the multi-dimensional transwell platform and defined culture media on prostate cellular proliferation, differentiation and signaling.

The p53 tumor suppressor protein protects against chemotherapeutic stress and apoptosis in human medulloblastoma cells.

Medulloblastoma (MB), a primitive neuroectodermal tumor, is the most common malignant childhood brain tumor and remains incurable in about a third of patients. Currently, survivors carry a significant burden of late treatment effects. The p53 tumor suppressor protein plays a crucial role in influencing cell survival in response to cellular stress and while the p53 pathway is considered a key determinant of anti-tumor responses in many tumors, its role in cell survival in MB is much less well defined. Herein, we report that the experimental drug VMY-1-103 acts through induction of a partial DNA damage-like response as well induction of non-survival autophagy. Surprisingly, the genetic or chemical silencing of p53 significantly enhanced the cytotoxic effects of both VMY and the DNA damaging drug, doxorubicin. The inhibition of p53 in the presence of VMY revealed increased late stage apoptosis, increased DNA fragmentation and increased expression of genes involved in apoptosis, including CAPN12 and TRPM8, p63, p73, BIK, EndoG, CIDEB, P27Kip1 and P21cip1. These data provide the groundwork for additional studies on VMY as a therapeutic drug and support further investigations into the intriguing possibility that targeting p53 function may be an effective means of enhancing clinical outcomes in MB.

p53 Modulates Notch Signaling in MCF-7 Breast Cancer Cells by Associating With the Notch Transcriptional Complex Via MAML1.

p53 and Notch-1 play important roles in breast cancer biology. Notch-1 inhibits p53 activity in cervical and breast cancer cells. Conversely, p53 inhibits Notch activity in T-cells but stimulates it in human keratinocytes. Notch co-activator MAML1 binds p53 and functions as a p53 co-activator. We studied the regulation of Notch signaling by p53 in MCF-7 cells and normal human mammary epithelial cells (HMEC). Results show that overexpression of p53 or activation of endogenous p53 with Nutlin-3 inhibits Notch-dependent transcriptional activity and Notch target expression in a dose-dependent manner. This effect could be partially rescued by transfection of MAML1 but not p300. Standard and quantitative co-immunoprecipitation experiments readily detected a complex containing p53 and Notch-1 in MCF-7 cells. Formation of this complex was inhibited by dominant negative MAML1 (DN-MAML1) and stimulated by wild-type MAML1. Standard and quantitative far-Western experiments showed a complex including p53, Notch-1, and MAML1. Chromatin immunoprecipitation (ChIP) experiments showed that p53 can associate with Notch-dependent HEY1 promoter and this association is inhibited by DN-MAML1 and stimulated by wild-type MAML1. Our data support a model in which p53 associates with the Notch transcriptional complex (NTC) in a MAML1-dependent fashion, most likely through a p53-MAML1 interaction. In our cellular models, the effect of this association is to inhibit Notch-dependent transcription. Our data suggest that p53-null breast cancers may lack this Notch-modulatory mechanism, and that therapeutic strategies that activate wild-type p53 can indirectly cause inhibition of Notch transcriptional activity.

The mitochondrial aspartate/glutamate carrier isoform 1 gene expression is regulated by CREB in neuronal cells.

The aspartate/glutamate carrier isoform 1 is an essential mitochondrial transporter that exchanges intramitochondrial aspartate and cytosolic glutamate across the inner mitochondrial membrane. It is expressed in brain, heart and muscle and is involved in important biological processes, including myelination. However, the signals that regulate the expression of this transporter are still largely unknown. In this study we first identify a CREB binding site within the aspartate/glutamate carrier gene promoter that acts as a strong enhancer element in neuronal SH-SY5Y cells. This element is regulated by active, phosphorylated CREB protein and by signal pathways that modify the activity of CREB itself and, most noticeably, by intracellular Ca(2+) levels. Specifically, aspartate/glutamate carrier gene expression is induced via CREB by forskolin while it is inhibited by the PKA inhibitor, H89. Furthermore, the CREB-induced activation of gene expression is increased by thapsigargin, which enhances cytosolic Ca(2+), while it is inhibited by BAPTA-AM that reduces cytosolic Ca(2+) or by STO-609, which inhibits CaMK-IV phosphorylation. We further show that CREB-dependent regulation of aspartate/glutamate carrier gene expression occurs in neuronal cells in response to pathological (inflammation) and physiological (differentiation) conditions. Since this carrier is necessary for neuronal functions and is involved in myelinogenesis, our results highlight that targeting of CREB activity and Ca(2+) might be therapeutically exploited to increase aspartate/glutamate carrier gene expression in neurodegenerative diseases.

Expanding the Clinical Spectrum of Mitochondrial Citrate Carrier (SLC25A1) Deficiency: Facial Dysmorphism in Siblings with Epileptic Encephalopathy and Combined D,L-2-Hydroxyglutaric Aciduria.

Recessive mutations in SLC25A1 encoding mitochondrial citrate carrier cause a rare inherited metabolic disorder, combined D,L-2-hydroxyglutaric aciduria (D,L-2-HGA), characterized by epileptic encephalopathy, respiratory insufficiency, developmental arrest and early death. Here, we describe two siblings compound heterozygotes for null/missense SLC25A1 mutations, c.18_24dup (p.Ala9Profs*82), and c.134C>T (p.Pro45Leu). These children presented with classic clinical features of D,L-2-HGA, but also showed marked facial dysmorphism. Additionally, there was prominent lactic acidosis in one of the siblings. Our observations suggest that facial dysmorphism is a previously unrecognized but an important diagnostic feature of SLC25A1 deficiency and expand the clinical phenotype linked to SLC25A1 mutations.

The induction of the p53 tumor suppressor protein bridges the apoptotic and autophagic signaling pathways to regulate cell death in prostate cancer cells.

The p53 tumor suppressor protein plays a crucial role in influencing cell fate decisions in response to cellular stress. As p53 elicits cell cycle arrest, senescence or apoptosis, the integrity of the p53 pathway is considered a key determinant of anti-tumor responses. p53 can also promote autophagy, however the role of p53-dependent autophagy in chemosensitivity is poorly understood. VMY-1-103 (VMY), a dansylated analog of purvalanol B, displays rapid and potent anti-tumor activities, however the pathways by which VMY works are not fully defined. Using established prostate cancer cell lines and novel conditionally reprogrammed cells (CRCs) derived from prostate cancer patients; we have defined the mechanisms of VMY-induced prostate cancer cell death. Herein, we show that the cytotoxic effects of VMY required a p53-dependent induction of autophagy, and that inhibition of autophagy abrogated VMY-induced cell death. Cancer cell lines harboring p53 missense mutations evaded VMY toxicity and treatment with a small molecule compound that restores p53 activity re-established VMY-induced cell death. The elucidation of the molecular mechanisms governing VMY-dependent cell death in cell lines, and importantly in CRCs, provides the rationale for clinical studies of VMY, alone or in combination with p53 reactivating compounds, in human prostate cancer.

A key role of the mitochondrial citrate carrier (SLC25A1) in TNFα- and IFNγ-triggered inflammation.

The chronic induction of inflammation underlies multiple pathological conditions, including metabolic, autoimmune disorders and cancer. The mitochondrial citrate carrier (CIC), encoded by the SLC25A1 gene, promotes the export of citrate from the mitochondria to the cytoplasm, a process that profoundly influences energy balance in the cells. We have previously shown that SLC25A1 is a target gene for lipopolysaccharide signaling and promotes the production of inflammatory mediators. We now demonstrate that SLC25A1 is induced at the transcriptional level by two key pro-inflammatory cytokines, tumor necrosis factor-α (TNFα) and interferon-γ (IFNγ), and such induction involves the activity of the nuclear factor kappa B and STAT1 transcription factors. By studying the down-stream events following SLC25A1 activation during signals that mimic inflammation, we demonstrate that CIC is required for regulating the levels of nitric oxide and of prostaglandins by TNFα or IFNγ. Importantly, we show that the citrate exported from mitochondria via CIC and its downstream metabolic intermediate, acetyl-coenzyme A, are necessary for TNFα or IFNγ to induce nitric oxide and prostaglandin production. These findings provide the first line of evidence that the citrate export pathway, via CIC, is central for cytokine-induced inflammatory signals and shed new light on the relationship between energy metabolism and inflammation.

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

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.