Amino Acids Regulate Cisplatin Insensitivity in Neuroblastoma

Abstract

Neuroblastoma are pediatric, extracranial malignancies showing alarming survival prognosis outcomes due to their resilience to current aggressive treatment regimens, including chemotherapies with cisplatin (CDDP) provided in the first line of therapy regimens. Metabolic deregulation supports tumor cell survival in drug-treated conditions. However, metabolic pathways underlying cisplatin-resistance are least studied in neuroblastoma. Our metabolomics analysis revealed that cisplatin-insensitive cells alter their metabolism; especially, the metabolism of amino acids was upregulated in cisplatin-insensitive cells compared to the cisplatin-sensitive neuroblastoma cell line. A significant increase in amino acid levels in cisplatin-insensitive cells led us to hypothesize that the mechanisms upregulating intracellular amino acid pools facilitate insensitivity in neuroblastoma. We hereby report that amino acid depletion reduces cell survival and cisplatin-insensitivity in neuroblastoma cells. Since cells regulate their amino acids levels through processes, such as autophagy, we evaluated the effects of hydroxychloroquine (HCQ), a terminal autophagy inhibitor, on the survival and amino acid metabolism of cisplatin-insensitive neuroblastoma cells. Our results demonstrate that combining HCQ with CDDP abrogated the amino acid metabolism in cisplatin-insensitive cells and sensitized neuroblastoma cells to sub-lethal doses of cisplatin. Our results suggest that targeting of amino acid replenishing mechanisms could be considered as a potential approach in developing combination therapies for treating neuroblastomas.

Identification of a Five-Gene Signature Derived From MYCN Amplification and Establishment of a Nomogram for Predicting the Prognosis of Neuroblastoma

“…KEGG pathway analysis showed that the DEGs were mainly enriched in cancer-related pathways, such as the amino acid metabolism and cell adhesion processes. Cancer cells require an abundant supply of amino acids to sustain their growth ( Vettore et al, 2020 ), and an increased amino acid metabolism has been observed in chemoresistant NB cell lines ( Gunda et al, 2020 ). The cancer metastatic cascade is dependent on the loss of adhesion between cells, resulting in the dissociation of the cell from the primary tumor ( Martin and Jiang, 2009 ).…”

Comparative Metabolomics Study of the Impact of Articaine and Lidocaine on the Metabolism of SH-SY5Y Neuronal Cells

“…Several other amino acids (phenylalanine, tyrosine, tryptophan, histidine) showed the same variation pattern upon ATC or LDC exposure, i.e., lower consumption and intracellular accumulation in LA-treated cells, again suggesting downregulation of TCA cycle anaplerotic fueling. Increased intracellular levels of amino acids in neuroblastoma cells have also been reported in response to other substances, such as the neurotoxic metabolite β-Methylamino-l-alanine (BMAA) [ 52 ] and the chemotherapy agent cisplatin [ 53 ]. In particular, cisplatin-resistant neuroblastoma cells showed heightened amino acid levels upon exposure to cisplatin, while cell survival and drug resistance decreased when the culture medium was deprived of essential amino acids.…”

Resistance to different anthracycline chemotherapeutics elicits distinct and actionable primary metabolic dependencies in breast cancer

“…Crucially, our study further upholds the viability of exploiting metabolic alterations associated with resistance to chemotherapeutic drugs to increase their success rate ( Zaal and Berkers, 2018 ). This strategy has already shown success in numerous cancers; for example, inhibition of amino acid recycling sensitized neuroblastomas to cisplatin ( Gunda et al, 2020 ), fueling histidine catabolism via histidine supplementation increases sensitivity of leukemic xenografts to methotrexate ( Kanarek et al, 2018 ), and the glutaminase inhibitor CB-839 synergistically enhances the cytotoxicity of carfilzomib in treatment-resistant multiple myeloma cells, notably through its inhibition of glutamine-fueled mitochondrial respiration ( Thompson et al, 2017 ).…”