Oncophosphosignaling Favors a Glycolytic Phenotype in Human Drug Resistant Leukemia

• Published in: Journal of cellular biochemistry 2017-11, Vol.118 (11), p.3846-3854
• Main Authors: Faria, Alessandra V.S., Tornatore, Thaís F., Milani, Renato, Queiroz, Karla C.S., Sampaio, Igor H., Fonseca, Emanuella M.B., Rocha‐Brito, Karin J.P., Santos, Tamira O., Silveira, Leonardo R., Peppelenbosch, Maikel P., Ferreira‐Halder, Carmen V.
• Format: Article
• Language: English
• Subjects: ACP1; Acute Disease; Addictions; BCR-ABL protein; Cell death; CHEMORESISTANT LEUKEMIA CELLS; Dehydrogenase; Dehydrogenases; Dephosphorylation; Drug resistance; Drug Resistance, Neoplasm; Enzymes; Fusion protein; Glucose; Glucose transporter; Glycolysis; GLYCOLYTIC METABOLISM; Humans; K562 Cells; KINOME; L-Lactate dehydrogenase; Lactate dehydrogenase; Lactic acid; Leukemia; Leukemia - metabolism; Leukemia - pathology; LMWPTP; Metabolism; Mitochondria; Molecular weight; Neoplasm Proteins - metabolism; Oxidation resistance; Oxidative metabolism; Phosphatase; Phosphorylation; Post-translation; Protein folding; Protein Tyrosine Phosphatases - metabolism; Protein-tyrosine-phosphatase; Proteins; Pyruvic acid; Signal Transduction; siRNA; Succinate dehydrogenase; Tyrosine
• ISSN: 0730-2312; 1097-4644
• DOI: 10.1002/jcb.26034

ABSTRACT In chemoresistant leukemia cells (Lucena‐1), the low molecular weight protein tyrosine phosphatase (LMWPTP) is about 20‐fold more active than in their susceptible counterpart (K562). We found this phosphatase ensures the activated statuses of Src and Bcr‐Abl. Since, phosphorylation and dephosphorylation of proteins represent a key post‐translational regulation of several enzymes, we also explored the kinome. We hereby show that LMWPTP superactivation, together with kinome reprogramming, cooperate towards glucose addiction. Resistant leukemia cells present lower levels of oxidative metabolism, in part due to downexpression of the following mitochondrial proteins: pyruvate dehydrogenase subunit alpha 1, succinate dehydrogenase, and voltage‐dependent anion channel. Those cells displayed higher expression levels of glucose transporter 1 and higher production of lactate. In addition, Lucena‐1 siRNA LMWPTP cells showed lower expression levels of glucose transporter 1 and lower activity of lactate dehydrogenase. On the other hand, K562 cells overexpressing LMWPTP presented higher expression/activity of both proteins. In this study, we show that LMWPTP is a pivotal mediator of metabolic reprogramming that confers survival advantages to leukemia cells against death stimuli. J. Cell. Biochem. 118: 3846–3854, 2017. © 2017 Wiley Periodicals, Inc. The metabolic reprogramming in which kinases and LMWPTP take part, gives survival advantages to leukemia cells towards death stimuli, once key metabolites are produced for tumor cells via accelerate glycolysis and truncated Krebs cycle.