CSIG-01Sab-MEDIATED SIGNALING INFLUENCES AEROBIC GLYCOLYSIS AND CHEMOSUSCEPTIBILITY IN HUMAN NEUROBLASTOMA CELLS

Abstract

BACKGROUND: Neuroblastoma is one of the most prevalent pediatric solid tumors and represents 10-15% of cancer deaths in children. Late stage neuroblastomas are commonly resistant to conventional treatments and most patients only experience transient effects of chemotherapy followed by a recurrence. Thus, new therapeutic options are needed to treat late stage neuroblastomas. Our recent studies have demonstrated that mitochondrial c-Jun N-terminal kinase (JNK) signaling on the outer mitochondrial scaffold protein Sab is an essential component of cell death. Intriguingly, Sab expression is down-regulated in neuroblastoma. We propose increasing mitochondrial JNK signaling by elevating Sab expression may be a novel method to improve therapeutic response in neuroblastoma patients. In our current study, we evaluate the impact of Sab mediated signaling on neuroblastoma physiology. RESULTS: Inhibition Sab-mediated signaling altered cellular metabolism in SH-SY5Y cells as determined by analyses. Treatment of SH-SY5Y cells with the Tat-SabKIM1 peptide, a peptide known to inhibit mitogen-activated protein kinases (MAPKs) on Sab, increased oxidation of both glucose and glutamine, while decreasing the extracellular acidification rate (ECAR). The shift in ECAR was not due to a change in lactate dehydrogenase levels in the cells. Further, the SH-SY5Y cells treated with the Tat-SabKIM1 peptide had more Bcl-2 proteins and less BH3-only proteins when compared to their counterparts dosed with a scrambled peptide. SH-SY5Y cells treated with the inhibitory Sab peptide also had reduced proliferation rates and were resistant to chemotherapy agents (carboplatin, cyclophosphamide, doxorubicin, and etoposide). Finally, examination of additional neuroblastoma cell lines revealed that Sab levels correspond to proliferation rate, metabolic phenotype, and chemo-sensitivity. CONCLUSIONS: Our studies demonstrate that mitochondrial Sab-mediated signaling is reduced in neuroblastoma patients; further, Sab-mediated signaling is a critical regulator of neuroblastoma growth, metabolism, and apoptosis. Consequently, increasing Sab expression represents a new approach to sensitize neuroblastoma cells to conventional therapies.