dorsomorphin and Leukemia

AMPK is generally a tumor suppressor. However, once cancer arises, AMPK becomes a tumor promoter instead, driving cancer development. For such AMPK-driven cancers, AMPK blockade may be a valuable therapeutic strategy. Here we show that AMPK is upregulated in a variety of hematological cancers and plays key roles in maintaining viability of tumor cells. Blockade of AMPK signaling by dorsomorphin markedly induces apoptosis in Jurkat, K562 cell lines as well as primary cancerous B cells. Mechanistically, dorsomorphin significantly upregulates the expression of BAD, a pro-apoptotic member of the Bcl-2 gene family involved in initiating apoptosis. Reduction of BAD expression by RNA interference prevents apoptosis in response to AMPK inhibition. Thus, our data found BAD integrates the pro-apoptotic effects of dorsomorphin and provided novel insights into the mechanisms by which AMPK facilitates survival signaling in hematologic tumor cells.

Topics: AMP-Activated Protein Kinases; Apoptosis; bcl-Associated Death Protein; Humans; Jurkat Cells; K562 Cells; Leukemia; Protein Kinase Inhibitors; Pyrazoles; Pyrimidines; Signal Transduction; Up-Regulation

The shift in energy metabolism from oxidative phosphorylation to glycolysis can serve as a target for the inhibition of cancer growth. Here, we examined the metabolic changes induced by 2-deoxyglucose (2-DG), a glycolysis inhibitor, in leukemia cells by metabolome analysis. NB4 cells mainly utilized glucose as an energy source by glycolysis and oxidative phosphorylation in mitochondria, since metabolites in the glycolytic pathway and in the tricarboxylic acid (TCA) cycle were significantly decreased by 2-DG. In THP-1 cells, metabolites in the TCA cycle were not decreased to the same extent by 2-DG as in NB4 cells, which indicates that THP-1 utilizes energy sources other than glucose. TCA cycle metabolites in THP-1 cells may be derived from acetyl-CoA by fatty acid β-oxidation, which was supported by abundant detection of carnitine and acetylcarnitine in THP-1 cells. 2-DG treatment increased the levels of pentose phosphate pathway (PPP) metabolites and augmented the generation of NADPH by glucose-6-phosphate dehydrogenase. An increase in NADPH and upregulation of glutathione synthetase expression resulted in the increase in the reduced form of glutathione by 2-DG in NB4 cells. We demonstrated that a combination of 2-DG and inhibition of PPP by dehydroepiandrosterone (DHEA) effectively suppressed the growth of NB4 cells. The replenishment of the TCA cycle by fatty acid oxidation by carnitine palmitoyltransferase in THP-1 cells, treated by 2-DG, might be regulated by AMPK, as the combination of 2-DG and inhibition of AMPK by compound C potently suppressed the growth of THP-1 cells. Although 2-DG has been effective in preclinical and clinical studies, this treatment has not been fully explored due to concerns related to potential toxicities such as brain toxicity at high doses. We demonstrated that a combination of 2-DG and DHEA or compound C at a relatively low concentration effectively inhibits the growth of NB4 and THP-1 cells, respectively. These observations may aid in the identification of appropriate combinations of metabolic inhibitors at low concentrations which do not cause toxicities.

Topics: Acetyl Coenzyme A; AMP-Activated Protein Kinases; Carnitine O-Palmitoyltransferase; Cell Line, Tumor; Citric Acid Cycle; Dehydroepiandrosterone; Deoxyglucose; Energy Metabolism; Fatty Acids; Glucose; Glucosephosphate Dehydrogenase; Glutathione; Glycolysis; Humans; Leukemia; Metabolome; Mitochondria; NADP; Oxidation-Reduction; Oxidative Phosphorylation; Pentose Phosphate Pathway; Pyrazoles; Pyrimidines