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Polyethylene glycol derivative 9bw suppresses growth of neuroblastoma cells by inhibiting oxidative phosphorylation.

ABSTRACT: Neuroblastoma (NB) is a childhood malignancy originating from the sympathetic nervous system, and accounts for approximately 15% of all pediatric cancer-related deaths. As the 5-y survival rate of patients with high-risk NB is <50%, novel therapeutic strategies for NB patients are urgently required. Nonaethylene glycol mono('4-iodo-4-biphenyl)ester (9bw) is a polyethylene glycol derivative, synthesized by modifying a compound originally extracted from filamentous bacteria. Although 9bw shows remarkable inhibition of tumor cell growth, the underlying mechanisms remain unclear. Here, we examined the efficacy of 9bw on human NB-derived cells, and investigated the molecular mechanisms underlying the cytotoxic effects of 9bw on these cells. Our results indicated that 9bw induced cell death in NB cells by decreasing the production of ATP. Metabolome analysis and measurement of oxygen consumption indicated that 9bw markedly suppressed oxidative phosphorylation (OXPHOS). Further analyses indicated that 9bw inhibited the activity of mitochondrial respiratory complex I. Moreover, we showed that 9bw inhibited growth of NB in vivo. Based on the results of the present study, 9bw is a good candidate as a novel agent for treatment of NB.

SUBMITTER: Nagasaki-Maeoka E

PROVIDER: S-EPMC7419032 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature

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Polyethylene glycol derivative 9bw suppresses growth of neuroblastoma cells by inhibiting oxidative phosphorylation.

Nagasaki-Maeoka Eri E Ikeda Kazuhiro K Takayama Ken-Ichi KI Hirano Takayuki T Ishizuka Yoshiaki Y Koshinaga Tsugumichi T Tsukune Naoya N Takayama Tadateru T Inoue Satoshi S Fujiwara Kyoko K

Cancer science 20200620 8

Neuroblastoma (NB) is a childhood malignancy originating from the sympathetic nervous system, and accounts for approximately 15% of all pediatric cancer-related deaths. As the 5-y survival rate of patients with high-risk NB is <50%, novel therapeutic strategies for NB patients are urgently required. Nonaethylene glycol mono('4-iodo-4-biphenyl)ester (9bw) is a polyethylene glycol derivative, synthesized by modifying a compound originally extracted from filamentous bacteria. Although 9bw shows rem ...[more]

PMID: 32495467

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Project description:BackgroundNeuroblastoma (NB), the most common extracranial solid malignancy in children, carries a poor prognosis in high-risk disease, thus requiring novel therapeutic approaches. Survivin is overexpressed in NB, has pro-mitotic and anti-apoptotic functions, and impacts on oxidative phosphorylation (OXPHOS) and aerobic glycolysis. The subcellular localization and hence function of survivin is directed by the GTPase Ran.AimTo determine efficacy and modes of action of the survivin-Ran inhibitor LLP-3 as a potential novel therapy of NB.MethodsSurvivin and Ran mRNA expression in NB tumors was correlated to patient survival. Response to LLP-3 in NB cell lines was determined by assays for viability, proliferation, apoptosis, clonogenicity and anchorage-independent growth. Interaction of survivin and Ran was assessed by proximity-linked ligation assay and their subcellular distribution by confocal immunofluorescence microscopy. Expression of survivin, Ran and proteins important for OXPHOS and glycolysis was determined by Western blot, hexokinase activity by enzymatic assay, interaction of survivin with HIF-1α by co-IP, and OXPHOS and glycolysis by extracellular flux analyzer.ResultsHigh mRNA expression of survivin and Ran is correlated with poor patient survival. LLP-3 decreases viability, induces apoptosis, and inhibits clonogenic and anchorage-independent growth in NB cell lines, including those with MYCN amplification, and mutations of p53 and ALK. LLP-3 inhibits interaction of survivin with Ran, decreasing their concentration both in the cytoplasm and the nucleus. LLP-3 impairs flexibility of energy metabolism by inhibiting both OXPHOS and glycolysis. Metabolic inhibition is associated with mitochondrial dysfunction and attenuated hexokinase activity but is independent of HIF-1α.ConclusionLLP-3 attenuates interaction and concentration of survivin and Ran in NB cells. It controls NB cells with diverse genetic alterations, associated with inhibition of OXPHOS, aerobic glycolysis, mitochondrial function and HK activity. Thus, LLP-3 warrants further studies as a novel drug against NB.

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Polyethylene glycol derivative 9bw suppresses growth of neuroblastoma cells by inhibiting oxidative phosphorylation.

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Polyethylene glycol derivative 9bw suppresses growth of neuroblastoma cells by inhibiting oxidative phosphorylation.

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