Inhibition of polyamine synthesis and uptake reduces tumor progression and prolongs survival in mouse models of neuroblastoma

Abstract

Amplification of the MYCN oncogene is associated with an aggressive phenotype and poor outcome in childhood neuroblastoma. Polyamines are highly regulated essential cations that are frequently elevated in cancer cells, and the rate-limiting enzyme in polyamine synthesis, ornithine decarboxylase 1 (ODC1), is a direct transcriptional target of MYCN. Treatment of neuroblastoma cells with the ODC1 inhibitor difluoromethylornithine (DFMO), although a promising therapeutic strategy, is only partially effective at impeding neuroblastoma cell growth due to activation of compensatory mechanisms resulting in increased polyamine uptake from the surrounding microenvironment. In this study, we identified solute carrier family 3 member 2 (SLC3A2) as the key transporter involved in polyamine uptake in neuroblastoma. Knockdown of SLC3A2 in neuroblastoma cells reduced the uptake of the radiolabeled polyamine spermidine, and DFMO treatment increased SLC3A2 protein. In addition, MYCN directly increased polyamine synthesis and promoted neuroblastoma cell proliferation by regulating SLC3A2 and other regulatory components of the polyamine pathway. Inhibiting polyamine uptake with the small-molecule drug AMXT 1501, in combination with DFMO, prevented or delayed tumor development in neuroblastoma-prone mice and extended survival in rodent models of established tumors. Our findings suggest that combining AMXT 1501 and DFMO with standard chemotherapy might be an effective strategy for treating neuroblastoma.

Enhancer hijacking determines intra- and extrachromosomal circularMYCNamplicon architecture in neuroblastoma

“…Functional studies have shown that both ODC1 and ALK are highly relevant in neuroblastoma 28,29 . Co-amplification with MYCN has been reported before 22 , but to our knowledge the clinical relevance of co-amplification had not been determined so far.…”

Immunophenotypic Profiles in Polycystic Ovary Syndrome

“…Subsequently, β-catenin activation triggers PI3K/Akt that, in turn, induces IL-10 production and inhibits IL-6 secretion [42]. By contrast, accumulating evidence implicates CD11c + HLA-DR + DCs as important cell components of the follicular fluid, and mature DCs were positively correlated to the ovary reaction to gonadotrophic, suggesting a function related to the aseptic inflammation in ovulation [43,44]. Also, the number of DCs in the follicular fluid was found to be significantly decreased in PCOS patients as compared to those in healthy controls [45].…”

“…Due to the accumulation of numerous follicles with no ovulation, patients with PCOS show a high level of estrogen without progesterone resistance. IL-6 can also stimulate the expression of the key transcription factors of Th17 cells by activating STAT3 and the expression of RORα and RORγ, thereby promoting the differentiation of Th0 cells to Th17 cells [43,73]. Though some information shows Th17 of PCOS is decreasing in animal models [74,75], in human PCOS, evidence focuses on the expansion of proinflammatory Th17 subset not only in the blood but also kidneys [75]; however, the reason is obscure.…”

SKP2, positively regulated by circ_ODC1/miR‐422a axis, promotes the proliferation of retinoblastoma

“…[10][11][12] Herein we assessed the expression of circ_ODC1 in RB and normal tissues. Through starBase2 (http://starbase.sysu.edu.cn/starbase2/index.php), we found circ_ODC1 to be the circular RNA (circRNA) that could bind to miR-422a.…”

“…Intriguingly, the host gene of circ_ODC1 has been reported as an oncogene in various cancers. [10][11][12] Herein we assessed the expression of circ_ODC1 in RB and normal tissues. The results of RT-qPCR indicated the upregulated expression of circ_ODC1 in RB tissues ( Figure 4A).…”