Abstract
LIN28 has emerged as an oncogenic driver in a number of cancers, including neuroblastoma (NB). Overexpression of LIN28 correlates with poor outcome in NB, therefore drugs that impact the LIN28/Let-7 pathway could be beneficial in treating NB patients. The LIN28/Let-7 pathway affects many cellular processes including the regulation of cancer stem cells and glycolytic metabolism. Polyamines, regulated by ornithine decarboxylase (ODC) modulate eIF-5A which is a direct regulator of the LIN28/Let-7 axis. We propose that therapy inhibiting ODC will restore balance to the LIN28/Let-7 axis, suppress glycolytic metabolism, and decrease MYCN protein expression in NB. Difluoromethylornithine (DFMO) is an inhibitor of ODC in clinical trials for children with NB. In vitro experiments using NB cell lines, BE(2)-C, SMS-KCNR, and CHLA90 show that DFMO treatment reduced LIN28B and MYCN protein levels and increased Let-7 miRNA and decreased neurosphere formation. Glycolytic metabolic activity decreased with DFMO treatment in vivo. Additionally, sensitivity to DFMO treatment correlated with LIN28B overexpression (BE(2)-C>SMS-KCNR>CHLA90). This is the first study to demonstrate that DFMO treatment restores balance to the LIN28/Let-7 axis and inhibits glycolytic metabolism and neurosphere formation in NB and that PET scans may be a meaningful imaging tool to evaluate the therapeutic effects of DFMO treatment.
Highlights
Neuroblastoma (NB) is a pediatric cancer that is generally diagnosed in children before the age of five [1]
Cell lines with high LIN28B/MYCN gene expression are more sensitive to DFMO treatment the least sensitive with an IC50 of 25.8 mM
Compared to BE(2)-C and SMS-KCNR cell lines, CHLA90 cells required a longer treatment time to show decreases in LIN28B and MYCN protein expression when treated with DFMO (Figure 3A)
Summary
Neuroblastoma (NB) is a pediatric cancer that is generally diagnosed in children before the age of five [1]. High risk NB patients are characterized by MYCN amplification, age greater than 18 months, unfavorable histology, and aggressive metastatic disease [2, 3]. With multimodal treatments these patients can achieve remission but many who go into remission will relapse, at which point long term survival is less than 10% [1]. ODC’s specific function is to convert the polyamine precursor ornithine into the polyamine putrescine. Little is known about the specific functions www.impactjournals.com/oncotarget of polyamines; preclinical and early studies targeting polyamines in cancer have yielded promising results [4, 8, 9]
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