Signalling mechanisms that regulate metabolic profile and autophagy of acute myeloid leukaemia cells

Abstract

Acute myeloid leukaemia (AML) comprises a heterogeneous group of hematologic neoplasms characterized by diverse combinations of genetic, phenotypic and clinical features representing a major challenge for the development of targeted therapies. Metabolic reprogramming, mainly driven by deregulation of the nutrient‐sensing pathways as AMPK, mTOR and PI3K/AKT, has been associated with cancer cells, including AML cells, survival and proliferation. Nevertheless, the role of these metabolic adaptations on the AML pathogenesis is still controversial. In this work, the metabolic status and the respective metabolic networks operating in different AML cells (NB‐4, HL‐60 and KG‐1) and their impact on autophagy and survival was characterized. Data show that whereas KG‐1 cells exhibited preferential mitochondrial oxidative phosphorylation metabolism with constitutive co‐activation of AMPK and mTORC1 associated with increased autophagy, NB‐4 and HL‐60 cells displayed a dependent glycolytic profile mainly associated with AKT/mTORC1 activation and low autophagy flux. Inhibition of AKT is disclosed as a promising therapeutical target in some scenarios while inhibition of AMPK and mTORC1 has no major impact on KG‐1 cells’ survival. The results highlight an exclusive metabolic profile for each tested AML cells and its impact on determination of the anti‐leukaemia efficacy and on personalized combinatory therapy with conventional and targeted agents.

mTOR Regulation of Metabolism in Hematologic Malignancies

“…This opposite mechanism of action might be partially explained by the different cell models used by these studies (U937 in the first; HL60, NB4, and THP-1 in the second) that can reflect the heterogeneity in genetic and clinical features of the AML. Indeed, Pereira et al confirmed this heterogeneity by measuring glycolysis of AML cell lines in correlation with Akt/mTOR and AMPK activation status, finding a fluctuation in the glycolytic flux across the different cell lines, correlated with a different intracellular signaling [64]. Of interest, in the KG1 cell line they found a simultaneous activation of AMPK and mTOR, subverting the canonical view that dictates an antithetic role for these two kinases [64].…”

The PI3K-Akt-mTOR Signaling Pathway in Human Acute Myeloid Leukemia (AML) Cells

“…In addition, Akt interacts with PDK1, influencing the entrance of pyruvate into the mitochondrial metabolism [77]. Akt may also affect oxidative phosphorylation; it was shown that Akt could promote an indirect oxidative phosphorylation through elevated levels of substrates essential to activity of the TCA cycle and oxidative phosphorylation, such as pyruvate, ADP, and NADH [78].…”

Targeting Metabolic Reprogramming in Acute Myeloid Leukemia

“…Enhanced glycolysis has been observed in AML cell lines and in human primary AML blasts [10], while both the phosphoinositide 3-kinase (PI3K)/serine-threonine protein kinase B (AKT) and the mammalian target of rapamycin (mTOR) seemingly contribute to this glycolytic metabolism [11,12]. It has also been reported that AML patients have a distinct glucose metabolic signature as well as six serum metabolites involved in the glycolytic pathway which were identified and proposed as new prognostic biomarkers in the subgroup of patients with normal cytogenetics [13].…”

“…Additionally, leukemic stem-cells (LSCs) might have a role in inducing insulin resistance and decreasing insulin secretion, in order to increase the supply of glucose to malignant cells, therefore inducing alterations of systemic physiology by co-opting systemic regulatory mechanisms in their favor [17]. Metabolic plasticity allows AML cells to balance between glycolysis and OXPHOS, however, these metabolic adaptations likely differ between AML sub-types [12] and also within leukemic cells from the same patient [18].…”

“…Furthermore, activating signals from the microenvironment, including chemokines and adhesion molecules, are also factors that contribute to this signaling pathway activation [58]. mTORC1 is found to be activated even in the absence of an elevated PI3K/AKT signaling [12,59]. In spite of this evidence, the role of AMPK, mTORC1 and/or PI3K/AKT in AML cells is still controversial, having both tumor-suppressor and -promoter functions been assigned to these actors [48,52,56,60,61,62,63,64,65].…”