Metabolism and function of polyamines in cancer progression

Sari, Ita Novita; Setiawan, Tania; Kim, Kwang Seock; Wijaya, Yoseph Toni; Cho, Kae Won; Kwon, Hyog Young

doi:10.1016/j.canlet.2021.06.020

Cited by 75 publications

(50 citation statements)

References 150 publications

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“…In addition to epigenetical regulation of gene transcription, arginine is a precursor for polyamine synthesis [ 36 ]. In cancer cells, polyamine metabolism is frequently dysregulated, which promotes transformation and tumor progression [ 37 , 38 ]. Inhibition of polyamine synthesis induces autonomous cancer cell death and enhances immune response [ 37 , 39 ].…”

Section: Discussionmentioning

confidence: 99%

Inhibition of NOS1 promotes the interferon response of melanoma cells

Liu

2022

J Transl Med

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Background NOS1 expression predicts poor prognosis in patients with melanoma. However, the molecular function of NOS1 in the type I IFN response and immune escape of melanoma is still unknown. Methods The CRISPR/Cas9 system was used to generate NOS1-knockout melanoma cells and the biological characteristics of NOS1-knockout cells were evaluated by MTT assay, clonogenic assay, EdU assay, and flow cytometric assay. The effect on tumor growth was tested in BALB/c-nu and C57BL/6 mouse models. The gene expression profiles were detected with Affymetrix microarray and RNA-seq and KEGG (Kyoto Encyclopedia of Genes and Genomes) and CLUE GO analysis was done. The clinical data and transcriptional profiles of melanoma patients from the public database TCGA (The Cancer Genome Atlas) and GEO (Gene Expression Omnibus, GSE32611) were analyzed by Qlucore Omics Explorer. Results NOS1 deletion suppressed the proliferation of melanoma A375 cells in culture, blocked cell cycling at the G0/G1 phase, and decreased the tumor growth in lung metastasis nodes in a B16 melanoma xenograft mouse model. Moreover, NOS1 knockout increased the infiltration of CD3+ immune cells in tumors. The transcriptomics analysis identified 2203 differential expression genes (DEGs) after NOS1 deletion. These DEGs indicated that NOS1 deletion downregulated mostly metabolic functions but upregulated immune response pathways. After inhibiting with NOS1 inhibitor N-PLA, melanoma cells significantly increased the response to IFN$$\upalpha $$ α by upregulation expression of IFN$$\upalpha $$ α simulation genes (ISGs), especially the components in innate immune signaling, JAK-STAT, and TOLL-LIKE pathway. Furthermore, these NOS1-regulating immune genes (NOS1-ISGs) worked as a signature to predict poor overall survival and lower response to chemotherapy in melanoma patients. Conclusion These findings provided a transcriptional evidence of NOS1 promotion on tumor growth, which is correlated with metabolic regulation and immune escape in melanoma cells.

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Section: Discussionmentioning

confidence: 99%

Inhibition of NOS1 promotes the interferon response of melanoma cells

Liu

2022

J Transl Med

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“…The accumulation of PSN observed in tumor cells could be related to the incorporation of putrescine and the fact that polyamine uptake is increased in cancer cells through Polyamine Transport Systems ( Novita Sari et al, 2021 ). Importantly, we observed that PSN were stable in an in vivo environment, maintaining an efficient association of the NAs, which were then successfully released inside the cells.…”

Section: Discussionmentioning

confidence: 99%

Zebrafish as a platform to evaluate the potential of lipidic nanoemulsions for gene therapy in cancer

et al. 2022

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Gene therapy is a promising therapeutic approach that has experienced significant groth in recent decades, with gene nanomedicines reaching the clinics. However, it is still necessary to continue developing novel vectors able to carry, protect, and release the nucleic acids into the target cells, to respond to the widespread demand for new gene therapies to address current unmet clinical needs. We propose here the use of zebrafish embryos as an in vivo platform to evaluate the potential of newly developed nanosystems for gene therapy applications in cancer treatment. Zebrafish embryos have several advantages such as low maintenance costs, transparency, robustness, and a high homology with the human genome. In this work, a new type of putrescine-sphingomyelin nanosystems (PSN), specifically designed for cancer gene therapy applications, was successfully characterized and demonstrated its potential for delivery of plasmid DNA (pDNA) and miRNA (miR). On one hand, we were able to validate a regulatory effect of the PSN/miR on gene expression after injection in embryos of 0 hpf. Additionally, experiments proved the potential of the model to study the transport of the associated nucleic acids (pDNA and miR) upon incubation in zebrafish water. The biodistribution of PSN/pDNA and PSN/miR in vivo was also assessed after microinjection into the zebrafish vasculature, demonstrating that the nucleic acids remained associated with the PSN in an in vivo environment, and could successfully reach disseminated cancer cells in zebrafish xenografts. Altogether, these results demonstrate the potential of zebrafish as an in vivo model to evaluate nanotechnology-based gene therapies for cancer treatment, as well as the capacity of the developed versatile PSN formulation for gene therapy applications.

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“…ASS1, another key enzyme in UC, not only promoted the growth and invasion of gastric cancer ( Tsai et al, 2018 ) and colorectal cancer ( Doubleday et al, 2021 ), but also inhibited the progression of HCC ( Kim et al, 2021 ). Additionally, some of the products of UC, such as NO and pyrimidine, has been reported to promote tumor initiation ( Lala and Chakraborty, 2001 ; Evageliou et al, 2016 ; Novita Sari et al, 2021 ). Therefore, the mechanism of ASS1 and CPS1 in liver cancer is still unclear, and further studies are needed.…”

Section: Introductionmentioning

confidence: 99%

Hepatocyte-Specific Knock-Out of Nfib Aggravates Hepatocellular Tumorigenesis via Enhancing Urea Cycle

Zhou

Wang

Mao

et al. 2022

Front. Mol. Biosci.

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Nuclear Factor I B (NFIB) has been reported to promote tumor growth, metastasis, and liver regeneration, but its mechanism in liver cancer is not fully elucidated. The present study aims to reveal the role of NFIB in hepatocellular carcinogenesis. In our study, we constructed hepatocyte-specific NFIB gene knockout mice with CRISPR/Cas9 technology (Nfib−/−; Alb-cre), and induced liver cancer mouse model by intraperitoneal injection of DEN/CCl4. First, we found that Nfib−/− mice developed more tumor nodules and had heavier livers than wild-type mice. H&E staining indicated that the liver histological severity of Nfib−/− group was more serious than that of WT group. Then we found that the differentially expressed genes in the tumor tissue between Nfib−/− mice and wild type mice were enriched in urea cycle. Furthermore, ASS1 and CPS1, the core enzymes of the urea cycle, were significantly upregulated in Nfib−/− tumors. Subsequently, we validated that the expression of ASS1 and CPS1 increased after knockdown of NFIB by lentivirus in normal hepatocytes and also promoted cell proliferation in vitro. In addition, ChIP assay confirmed that NFIB can bind with promoter region of both ASS1 and CPS1 gene. Our study reveals for the first time that hepatocyte-specific knock-out of Nfib aggravates hepatocellular tumor development by enhancing the urea cycle.

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Metabolism and function of polyamines in cancer progression

Cited by 75 publications

References 150 publications

Inhibition of NOS1 promotes the interferon response of melanoma cells

Inhibition of NOS1 promotes the interferon response of melanoma cells

Zebrafish as a platform to evaluate the potential of lipidic nanoemulsions for gene therapy in cancer

Hepatocyte-Specific Knock-Out of Nfib Aggravates Hepatocellular Tumorigenesis via Enhancing Urea Cycle

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