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Gambogic acid sensitizes gemcitabine efficacy in pancreatic cancer by reducing the expression of ribonucleotide reductase subunit-M2 (RRM2).

ABSTRACT: Pancreatic cancer is susceptible to gemcitabine resistance, and patients receive less benefit from gemcitabine chemotherapy. Previous studies report that gambogic acid possesses antineoplastic properties; however, to our knowledge, there have been no specific studies on its effects in pancreatic cancer. Therefore, the purpose of this study was to explore whether increases the sensitivity of pancreatic cancer to gemcitabine, and determine the synergistic effects of gambogic acid and gemcitabine against pancreatic cancer.The effects of gambogic acid on cell viability, the cell cycle, and apoptosis were assessed using 4,5-dimethylthiazol-2-yl)-3,5-diphenylformazan (MTT) and flow cytometry in pancreatic cancer cell lines. Protein expression was detected by western blot analysis and mRNA expression was detected using q-PCR. A xenograft tumor model of pancreatic cancer was used to investigate the synergistic effects of gambogic acid and gemcitabine.Gambogic acid effectively inhibited the growth of pancreatic cancer cell lines by inducing S-phase cell cycle arrest and apoptosis. Synergistic activity of gambogic acid combined with gemcitabine was observed in PANC-1 and BxPC-3 cells based on the results of MTT, colony formation, and apoptosis assays. Western blot results demonstrated that gambogic acid sensitized gemcitabine-induced apoptosis by enhancing the expression of cleaved caspase-3, cleaved caspase-9, cleaved-PARP, and Bax, and reducing the expression of Bcl-2. In particular, gambogic acid reduced the expression of the ribonucleotide reductase subunit-M2 (RRM2) protein and mRNA, a trend that correlated with resistance to gemcitabine through inhibition of the extracellular signal-regulated kinase (ERK)/E2F1 signaling pathway. Treatment with gambogic acid and gemcitabine significantly repressed tumor growth in the xenograft pancreatic cancer model. Immunohistochemistry results demonstrated a downregulation of p-ERK, E2F1, and RRM2 in mice receiving gambogic acid treatment and combination treatment.These results demonstrate that gambogic acid sensitizes pancreatic cancer cells to gemcitabine in vitro and in vivo by inhibiting the activation of the ERK/E2F1/RRM2 signaling pathway. The results also indicate that gambogic acid treatment combined with gemcitabine might be a promising chemotherapy strategy for pancreatic cancer.

SUBMITTER: Xia G

PROVIDER: S-EPMC5553806 | biostudies-other | 2017 Aug

REPOSITORIES: biostudies-other

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Gambogic acid sensitizes gemcitabine efficacy in pancreatic cancer by reducing the expression of ribonucleotide reductase subunit-M2 (RRM2).

Xia Guanggai G Wang Hongcheng H Song Ziliang Z Meng Qingcai Q Huang Xiuyan X Huang Xinyu X

Journal of experimental & clinical cancer research : CR 20170810 1

<h4>Background</h4>Pancreatic cancer is susceptible to gemcitabine resistance, and patients receive less benefit from gemcitabine chemotherapy. Previous studies report that gambogic acid possesses antineoplastic properties; however, to our knowledge, there have been no specific studies on its effects in pancreatic cancer. Therefore, the purpose of this study was to explore whether increases the sensitivity of pancreatic cancer to gemcitabine, and determine the synergistic effects of gambogic aci ...[more]

PMID: 28797284

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Project description:Although there are molecularly distinct subtypes of prostate cancer, no molecular classification system is used clinically. The ribonucleotide reductase small subunit M2 (RRM2) gene plays an oncogenic role in many cancers. Our previous study elucidated comprehensive molecular mechanisms of RRM2 in prostate cancer (PC). Given the potent functions of RRM2, we set out to determine whether the RRM2 signature can be used to identify aggressive subtypes of PC. We applied gene ontology and pathway analysis in RNA-seq datasets from PC cells overexpressing RRM2. We refined the RRM2 signature by integrating it with two molecular classification systems (PCS and PAM50 subtypes) that define aggressive PC subtypes (PCS1 and luminal B) and correlated signatures with clinical outcomes in six published cohorts comprising 4000 cases of PC. Increased expression of genes in the RRM2 signature was significantly correlated with recurrence, high Gleason score, and lethality of PC. Patients with high RRM2 levels showed higher PCS1 score, suggesting the aggressive PC feature. Consistently, RRM2-regulated genes were highly enriched in the PCS1 signature from multiple PC cohorts. A simplified RRM2 signature (12 genes) was identified by intersecting the RRM2 signature, PCS1 signature, and the PAM50 classifier. Intriguingly, inhibition of RRM2 specifically targets PCS1 and luminal B genes. Furthermore, 11 genes in the RRM2 signature were correlated with enzalutamide resistance by using a single-cell RNA-seq dataset from PC circulating tumor cells. Finally, high expression of RRM2 was associated with an immunosuppressive tumor-immune microenvironment in both primary prostate cancer and metastatic prostate cancer using CIBERSORT analysis and LM22, a validated leukocyte gene signature matrix. These data demonstrate that RRM2 is a driver of aggressive prostate cancer subtypes and contributes to immune escape, suggesting that RRM2 inhibition may be of clinical benefit for patients with PC.

Project description:BackgroundRecent studies have identified ribonucleotide reductase subunit M2 (RRM2) as a putative promoter of tumors. However, no systematic analysis of its carcinogenicity has been conducted.MethodsThe potential functions of RRM2 in various tumor types were investigated using data from the Genotype-Tissue Expression (GTEx), the Clinical Proteomic Tumor Analysis Consortium (CPTAC), the Cancer Genome Atlas (TCGA), the Human Protein Atlas (HPA), cBioPortal, GEPIA, String, and Gene Set Enrichment Analysis (GSEA). We analyzed the difference in mRNA and protein expression, pathological stage, survival, mutation, tumor microenvironment (TME), and immune cell infiltration in relation to RRM2. Meanwhile, using TCGA and the Tumor Immune Estimation Resource 2 (TIMER 2), the associations between RRM2 expression, immune infiltration, and immune-related genes were assessed. Additionally, CCK-8, Edu and RT-PCR assays were used to validate that RRM2 acts as an oncogene in liver cancer cells and its association with HBx. A cohort of liver hepatocellular carcinoma (LIHC) patients (n=154) from Huashan Hospital was analyzed for the expression of RRM2 and the association between RRM2 and immune infiltration.ResultsUsing the GTEx and TCGA databases, we discovered that 28 tumors expressed RRM2 at significantly higher levels than the corresponding normal tissues. Increased RRM2 expression may be predictive of a poor overall survival (OS) in patients with seven different cancers. GO, KEGG, and GSEA analyses revealed that the biological process of RRM2 was associated with the regulation of carcinogenic processes and immune pathways in a variety of tumor types. The expression of RRM2 was highly correlated with maker genes involved in immune activation and immunosuppression, immune checkpoints, DNA mismatch repair system (MMR), and the infiltration levels of Tregs and macrophages (TAMs), suggesting that the carcinogenic effect of RRM2 may be achieved by regulating immune related genes. Moreover, as demonstrated by CCK-8 and Edu assays, RRM2 was an oncogene in liver cancer cells. We confirmed for the first time that RRM2 was significantly upregulated by HBx, suggesting that RRM2 may be a key regulator of LIHC induced by HBV. IHC analysis validated the upregulated expression of RRM2 protein and its correlation with immune infiltration makers in a LIHC patient cohort.ConclusionRRM2 may be a valuable molecular biomarker for predicting prognosis and immunotherapeutic efficacy in pan-cancer, particularly in LIHC.

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Gambogic acid sensitizes gemcitabine efficacy in pancreatic cancer by reducing the expression of ribonucleotide reductase subunit-M2 (RRM2).

Publications

Gambogic acid sensitizes gemcitabine efficacy in pancreatic cancer by reducing the expression of ribonucleotide reductase subunit-M2 (RRM2).

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