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Knockdown of STAT1 in SCC61 tumor xenografts leads to alterations in the expression of energy metabolic pathways

ABSTRACT: Background: Signal Transducer and Activator of Transcription 1 (STAT1) has traditionally been regarded as a transmitter of interferon signaling and a pro-apoptotic tumor suppressor. Recent data have identified new functions of STAT1 associated with tumorigenesis and resistance to genotoxic stress, including ionizing radiation (IR) and chemotherapy. To investigate the mechanisms contributing to the tumorigenic functions of STAT1, we performed a combined transcriptomic-proteomic expressional analysis and found that STAT1 is associated with regulation of energy metabolism. Methods: We generated a stable knockdown of STAT1 in the SCC61 human squamous cell carcinoma cell line, established tumor xenografts in athymic mice, and compared transcriptomic and proteomic profiles of STAT1 wild-type (WT) and knockdown (KD) untreated or irradiated (IR) tumors. Transcriptional profiling was based on Affymetrix Human GeneChip® Gene 1.0 ST microarrays. Proteomes were determined from the MS/MS data by searching against the human subset of the UniProt database. Data were analyzed using Significance Analysis of Microarrays (SAM) for RNA and Visualize software for proteins. Functional analysis was performed with Ingenuity Pathway Analysis (IPA) with statistical significance measured by Fisher’s exact test. Results: Knockdown of STAT1 led to significant growth suppression in untreated tumors and radiosensitization of irradiated tumors. These changes were accompanied by alterations in the expression of genes and proteins of glycolysis (GG), the citrate cycle (CC) and oxidative phosphorylation (OP). Of these pathways, GG had the most concordant changes in gene and protein expression and demonstrated a STAT1-dependent expression of genes and proteins consistent with tumor-specific glycolysis. IR drastically suppressed the GG pathway in STAT1 KD tumors without significant change in STAT1 WT tumors. The STAT1 and glycolytic pathways were co-expressed in human breast tumors, and expression of STAT1-linked glycolytic genes was highly predictive of poor prognosis. Conclusions: Our results identify a previously uncharacterized function of STAT1 in tumors: expressional regulation of genes and enzymes involved in glycolysis, the citrate cycle, and mitochondrial oxidative phosphorylation, with predominant regulation of glycolysis. STAT1-dependent transcriptional and translational regulation of glycolysis suggests a potential role for STAT1 as a transcriptional modulator of genes responsible for the Warburg effect.

ORGANISM(S): Homo sapiens

PROVIDER: GSE15845 | GEO | 2009/04/28

SECONDARY ACCESSION(S): PRJNA116821

REPOSITORIES: GEO

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Project description:Many cancers rely on glycolytic metabolism to fuel rapid proliferation. This has spurred interest in designing drugs that target tumor glycolysis such as AZD3965, a small molecule inhibitor of Monocarboxylate Transporter 1 (MCT1) currently undergoing Phase I evaluation for cancer treatment. Since MCT1 mediates proton-linked transport of monocarboxylates such as lactate and pyruvate across the plasma membrane (Halestrap and Meredith, 2004), AZD3965 is thought to block tumor growth through disruption of lactate transport and glycolysis. Here we show that MCT1 inhibition impairs proliferation of glycolytic breast cancer cells that express MCT4 via disruption of pyruvate rather than lactate export. We found that MCT1 expression is elevated in glycolytic breast tumors and cell lines as well as in malignant breast and lung tissues. High MCT1 expression predicts poor prognosis in breast and lung cancer patients. Stable knockdown and AZD3965-mediated inhibition of MCT1 promote oxidative metabolism. Acute inhibition of MCT1 reduces pyruvate export rate but does not consistently alter lactate transport or glycolytic flux in breast cancer cells that also express MCT4. Despite the lack of glycolysis impairment, MCT1 loss-of-function decreases breast cancer cell proliferation and blocks growth of mammary fat pad xenograft tumors. Our data suggest that MCT1 expression is elevated in glycolytic cancers to promote pyruvate export, which when inhibited enhances oxidative metabolism and reduces proliferation. This study presents an alternative molecular consequence of MCT1 inhibitors that further supports their use as anti-cancer therapeutics. Since MCT1 levels are elevated in glycolytic and malignant breast tumors, we hypothesized that MCT1 may contribute to the Warburg effect metabolic phenotype. To test this hypothesis, we generated whole genome microarray data from breast cancer cell lines either a) expressing a short hairpin (sh)RNA-mediated stable knockdown of MCT1; or b) treated for 24 hours with an MCT1 inhibitor (AZD3965). Scramble shRNA or DMSO were used as controls, and all conditions were analzed in triplicate. The cell lines used â HS578T, SUM149PT, and SUM159PT â are among the most glycolytic in a panel of 31 breast cancer cell lines.

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Knockdown of STAT1 in SCC61 tumor xenografts leads to alterations in the expression of energy metabolic pathways

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