Targeting ornithine decarboxylase reverses the LIN28/Let-7 axis and inhibits glycolytic metabolism in neuroblastoma

// Ann M. Lozier 1 , Maria E. Rich 1 , Anissa Pedersen Grawe 1 , Anderson S. Peck 2 , Ping Zhao 1 , Anthony Ting-Tung Chang 2 , Jeffrey P. Bond 3 and Giselle Saulnier Sholler 1,4 1 Pediatric Oncology Translational Research Program, Helen DeVos Children’s Hospital, Grand Rapids, MI, USA 2 Small Animal Imaging Facility, Van Andel Institute, Grand Rapids, MI, USA 3 University of Vermont, Michigan State University, Grand Rapids, MI, USA 4 College of Human Medicine, Michigan State University, Grand Rapids, MI, USA Correspondence: Giselle Saulnier Sholler, email: // Keywords : neuroblastoma, DFMO, LIN28B, glycolytic metabolism, stem cells Received : October 29, 2014 Accepted : November 14, 2014 Published : November 15, 2014 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.