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Targeted Inhibition of Purine Metabolism Is Effective in Suppressing Hepatocellular Carcinoma Progression.

ABSTRACT: Tumor-specific metabolic rewiring, acquired to confer a proliferative and survival advantage over nontransformed cells, represents a renewed focus in cancer therapy development. Hepatocellular carcinoma (HCC), a malignancy that has hitherto been resistant to compounds targeting oncogenic signaling pathways, represents a candidate cancer to investigate the efficacy of selectively antagonizing such adaptive metabolic reprogramming. To this end, we sought to characterize metabolic changes in HCC necessary for tumorigenesis. We analyzed gene expression profiles in three independent large-scale patient cohorts who had HCC. We identified a commonly deregulated purine metabolic signature in tumors with the extent of purine biosynthetic enzyme up-regulation correlated with tumor grade and a predictor of clinical outcome. The functional significance of enhanced purine metabolism as a hallmark in human HCC was then validated using a combination of HCC cell lines, patient-derived xenograft (PDX) organoids, and mouse models. Targeted ablation of purine biosynthesis by knockdown of the rate-limiting enzyme inosine-5'-monophosphate dehydrogenase (IMPDH) or using the drug mycophenolate mofetil (MMF) reduced HCC proliferation in vitro and decreased the tumor burden in vivo. In comparing the sensitivities of PDX tumor organoids to MMF therapy, we found that HCC tumors defined by high levels of IMPDH and guanosine nucleosides were most susceptible to treatment. Mechanistically, a phosphoinositide 3-kinase (PI3K)-E2F transcription factor 1 (E2F1) axis coordinated purine biosynthetic enzyme expression, deregulation of which altered the activity of mitogen-activated protein kinase/RAS signaling. Simultaneously abolishing PI3K signaling and IMPDH activity with clinically approved inhibitors resulted in greatest efficacy in reducing tumor growth in a PDX mouse model. Conclusion: Enhanced purine metabolic activity regulated by PI3K pathway-dependent activation of E2F1 promotes HCC carcinogenesis, suggesting the potential for targeting purine metabolic reprogramming as a precision therapeutic strategy for patients with HCC.

SUBMITTER: Chong YC

PROVIDER: S-EPMC7471427 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature

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Targeted Inhibition of Purine Metabolism Is Effective in Suppressing Hepatocellular Carcinoma Progression.

Chong Yong Chun YC Toh Tan Boon TB Chan Zhiling Z Lin Quy Xiao Xuan QXX Thng Dexter Kai Hao DKH Hooi Lissa L Ding Zhaobing Z Shuen Timothy T Toh Han Chong HC Dan Yock Young YY Bonney Glenn Kunnath GK Zhou Lei L Chow Pierce P Wang Yulan Y Benoukraf Touati T Chow Edward Kai-Hua EK Han Weiping W

Hepatology communications 20200727 9

Tumor-specific metabolic rewiring, acquired to confer a proliferative and survival advantage over nontransformed cells, represents a renewed focus in cancer therapy development. Hepatocellular carcinoma (HCC), a malignancy that has hitherto been resistant to compounds targeting oncogenic signaling pathways, represents a candidate cancer to investigate the efficacy of selectively antagonizing such adaptive metabolic reprogramming. To this end, we sought to characterize metabolic changes in HCC ne ...[more]

PMID: 32923839

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Project description:BackgroundDeregulated purine metabolism is critical for fast-growing tumor cells by providing nucleotide building blocks and cofactors. Importantly, purine antimetabolites belong to the earliest developed anticancer drugs and are still prescribed in clinics today. However, these antimetabolites can inhibit non-tumor cells and cause undesired side effects. As liver has the highest concentration of purines, it makes liver cancer a good model to study important nodes of dysregulated purine metabolism for better patient selection and precisive cancer treatment.MethodsBy using a training dataset from TCGA, we investigated the differentially expressed genes (DEG) of purine metabolism pathway (hsa00230) in hepatocellular carcinoma (HCC) and determined their clinical correlations to patient survival. A prognosis model was established by Lasso-penalized Cox regression analysis, and then validated through multiple examinations including Cox regression analysis, stratified analysis, and nomogram using another ICGC test dataset. We next treated HCC cells using chemical drugs of the key enzymes in vitro to determine targetable candidates in HCC.ResultsThe DEG analysis found 43 up-regulated and 2 down-regulated genes in the purine metabolism pathway. Among them, 10 were markedly associated with HCC patient survival. A prognostic correlation model including five genes (PPAT, DCK, ATIC, IMPDH1, RRM2) was established and then validated using the ICGC test dataset. Multivariate Cox regression analysis found that both prognostic risk model (HR = 4.703 or 3.977) and TNM stage (HR = 2.303 or 2.957) independently predicted HCC patient survival in the two datasets respectively. The up-regulations of the five genes were further validated by comparing between 10 pairs of HCC tissues and neighboring non-tumor tissues. In vitro cellular experiments further confirmed that inhibition of IMPDH1 significantly repressed HCC cell proliferation.ConclusionIn summary, this study suggests that purine metabolism is deregulated in HCC. The prognostic gene correlation model based on the five purine metabolic genes may be useful in predicting HCC prognosis and patient selection. Moreover, the deregulated genes are targetable by specific inhibitors.

Project description:BackgroundHepatocellular carcinoma (HCC) is still the most common cause of tumor-related death worldwide and accumulating studies report that long non-coding RNAs (LncRNAs) are closely related with HCC development, metastasis and prognosis. Cisplatinum, a well-known chemotherapeutic drug, has been widely used for treatment of numerous human cancers including HCC. This study aimed to investigate the differential expressions of LncRNAs in HCC cells treated with cisplatinum and its underlying mechanism.MethodsThe differential expressions of LncRNAs in HCC cells treated with cisplatinum were determined by RNA-seq. The roles of TPTEP1 in HCC development by applying gene function gain and loss analysis in MHCC97H and QYG-7703 cell lines were detected by quantitative real-time polymerase chain reaction (qRT-PCR), cell proliferation, colony formation, cell invasion and flow cytometry assays. The underlying mechanism of TPTEP1 sensitizing hepatocellular carcinoma cells to cisplatinum was examined by RNA-pull down, western blotting, subcellular fractionation, RNA immunoprecipitation and dual luciferase reporter assays. The effect of TPTEP1 on tumorigenesis in vivo was performed with a subcutaneous xenograft mouse model of HCC. In addition, TPTEP1 expression was detected in clinical tumor tissue samples by qRT-PCR.ResultsLncRNA TPTEP1 was highly expressed in cisplatinum-treated HCC cells, which sensitizes hepatocellular carcinoma cell to cisplatinum-induced apoptosis. TPTEP1 overexpression inhibited, while TPTEP1 knockdown promoted HCC cell proliferation, tumorigenicity and invasion. Furthermore, TPTEP1 exerted its tumor suppressing activities by interacting with signal transducer and activator of transcription 3 (STAT3) to inhibit its phosphorylation, homodimerization, nuclear translocation and down-stream genes transcription. Moreover, TPTEP1 overexpression obviously inhibits tumor masses in vivo in a subcutaneous xenograft mouse model of HCC and TPTEP1 is frequently downregulated in HCC tissues, compared to its corresponding pre-tumor tissues.ConclusionLncRNA TPTEP1 inhibits hepatocellular carcinoma cells progression by affecting IL-6/STAT3 signaling. Taken together, our findings suggest a tumor suppressing role of TPTEP1 in HCC progression and provide a novel understanding of TPTEP1 during the chemotherapy for HCC.

Dataset Information

Targeted Inhibition of Purine Metabolism Is Effective in Suppressing Hepatocellular Carcinoma Progression.

Publications

Targeted Inhibition of Purine Metabolism Is Effective in Suppressing Hepatocellular Carcinoma Progression.

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