Antitumor effects of the small molecule DMAMCL in neuroblastoma via suppressing aerobic glycolysis and targeting PFKL

Abstract

Background Neuroblastoma (NB) is a common solid malignancy in children that is associated with a poor prognosis. Although the novel small molecular compound Dimethylaminomicheliolide (DMAMCL) has been shown to induce cell death in some tumors, little is known about its role in NB. Methods We examined the effect of DMAMCL on four NB cell lines (NPG, AS, KCNR, BE2). Cellular confluence, survival, apoptosis, and glycolysis were detected using Incucyte ZOOM, CCK-8 assays, Annexin V-PE/7-AAD flow cytometry, and Seahorse XFe96, respectively. Synergistic effects between agents were evaluated using CompuSyn and the effect of DMAMCL in vivo was evaluated using a xenograft mouse model. Phosphofructokinase-1, liver type (PFKL) expression was up- and down-regulated using overexpression plasmids or siRNA. Results When administered as a single agent, DMAMCL decreased cell proliferation in a time- and dose-dependent manner, increased the percentage of cells in SubG1 phase, and induced apoptosis in vitro, as well as inhibiting tumor growth and prolonging survival in tumor-bearing mice (NGP, BE2) in vivo. In addition, DMAMCL exerted synergistic effects when combined with etoposide or cisplatin in vitro and displayed increased antitumor effects when combined with etoposide in vivo compared to either agent alone. Mechanistically, DMAMCL suppressed aerobic glycolysis by decreasing glucose consumption, lactate excretion, and ATP production, as well as reducing the expression of PFKL, a key glycolysis enzyme, in vitro and in vivo. Furthermore, PFKL overexpression attenuated DMAMCL-induced cell death, whereas PFKL silencing promoted NB cell death. Conclusions The results of this study suggest that DMAMCL exerts antitumor effects on NB both in vitro and in vivo by suppressing aerobic glycolysis and that PFKL could be a potential target of DMAMCL in NB.

Molecular pathway of anticancer effect of next-generation HSP90 inhibitors XL-888 and Debio0932 in neuroblastoma cell line

“…Similarly, Debio0932 led to a reduction in LPL gene expression. Genes such as ACLY, CPT2, G6PD LPL and PFKL are part of metabolic pathways such as lipid metabolism and energy production [ 53 – 55 ] . Therefore, XL-888 increasing the expression of these genes may result in acceleration or enhancement of these metabolic processes.…”

Development and Validation of a 6-Gene Hypoxia-Related Prognostic Signature For Cholangiocarcinoma

“…The production of lactate constitutes a local acidic environment for tumor cell proliferation and activates the cascade reaction of protein hydrolases to convert pre-matrix metalloproteinases into matrix metalloproteinases, which promote the degradation of the extracellular matrix of cancer cells and facilitate the invasion of surrounding tissues by tumor cells ( 38 ). A number of cancers have been identified to have PFKL as a component of the glycolysis process, including lung cancer ( 39 ), esophageal cancer ( 40 ), neuroblastoma ( 41 ) and hepatocellular carcinoma ( 42 ). The Bcl-2 protein family is one of the core regulatory mechanisms of apoptosis, which can receive and transmit intrinsic intracellular signals or external environmental stress signals, such as nutrient or hypoxic stress, DNA damage, oncogene over-activation, endoplasmic reticulum stress, etc ( 43 ).…”

Necdin, one of the important pathway proteins in the regulation of osteosarcoma progression by microRNA-200c

“…Flow cytometric was used to measure apoptosis. The Annexin V Phycoerythrin/7-amino-actinomycin D apoptosis detection kit (Sizhengbai, Beijing, China) was used for AnnexinV staining [ 24 , 25 ]. Briefly, 100 µL of cell suspension (control and miR-200c groups) was mixed with 5 µL of PE staining solution.…”