Cell intrinsic and extrinsic regulation of leukemia cell metabolism

Abstract

consumption through glycolysis even in the presence of oxygen (aerobic glycolysis) was initially hypothesized to be due to defective mitochondria [2]. However, more recent studies have established that many cancer cells harbor and are dependent upon functional mitochondria [3][4][5][6]. The question why cancer cells preferentially use glycolysis, an uneconomical route to produce ATP compared to mitochondrial oxidative phosphorylation, is beginning to be addressed in cancer cells. Glycolysis is not the dominant mechanism for many cancer cells to produce ATP, and ATP production is not the limiting factor for proliferation [7]. Rather, glycolysis offers cancer cells with metabolites essential for rapid division through metabolic pathways that branch away from glycolysis. For example, glucose-6-phosphate can be diverted to the pentose phosphate pathway (PPP) to produce reducing agents NADPH and ribonucleotides [8]. Additionally, 3-phospho-glycerate can enter the one-carbon cycle to generate amino acids, lipids, and reducing agents [9]. Thus, increased glycolysis meets the demand of proliferative cancer cells for anabolism, producing metabolic intermediates through multiple branching pathways. The decision of how cancer cells divert glycolysis intermediates remains elusive, but it is likely to be affected by cellular metabolic state and the environment in which the cancer cells are exposed.The metabolic milieu of the tumor microenvironment dictates the behavior of tumors. Tumors are exposed to nutrient-and oxygen-poor conditions as they grow exponentially due to insufficient vascularization [10]. Metabolic adaptation to these stress conditions is vital for tumor survival and expansion, and as such multiple metabolic regulators that enable metabolic adaptation are dysregulated in cancer. These include the components of the phosphatidylinositol 3-kinase (PI3K)/Akt signaling that feeds into the mechanistic target of rapamycin (mTOR) pathway, Abstract Metabolic homeostasis is a fundamental property of cells that becomes dysregulated in cancer to meet the altered, often heightened, demand for metabolism for increased growth and proliferation. Oncogenic mutations can directly change cellular metabolism in a cell-intrinsic manner, priming cells for malignancy. Additionally, cellextrinsic cues from the microenvironment, such as hypoxia, nutrient availability, oxidative stress, and crosstalk from surrounding cells can also affect cancer cell metabolism, and produce metabolic heterogeneity within the tumor. Here, we highlight recent findings revealing the complexity and adaptability of leukemia cells to coordinate metabolism.

AMPK promotes the survival of colorectal cancer stem cells

“…Under certain conditions and/or at certain stage of tumorigenesis, AMPK may play a role in preventing tumor formation . However, more and more evidence indicate that AMPK is probably more important for the survival of cancer cells and cancer stem cells by reprogramming their metabolism in order to adapt to their uncontrolled proliferating nature and better cope with the intrinsic and extrinsic metabolic stress . Therefore based on the latter role of AMPK, we propose that inhibition of AMPK may help to eradicate cancer stem cells and prevent tumors from metastasizing and relapsing.…”

mTOR Regulation of Metabolism in Hematologic Malignancies

“…Recently, several authors have shown that many of the Signal Transduction Pathways (STPs) aberrantly activated in cancer cells actually converge on the deregulation of common metabolic mechanisms responsible for cell growth and survival [40,48,49]. The instructional metabolic reprogramming from signaling is critical for cellular homeostasis and cell fate.…”

Six1 regulates leukemia stem cell maintenance in acute myeloid leukemia

“…It was shown that SIX1 directly binds to the promoter region of most glycolytic genes and increases the expression of these genes in solid tumors, thus promoting glycolysis and tumor growth in vitro and in vivo . Increased glycolysis is overall observed in multiple hematological malignancies, including AML, ALL, CLL and multiple myeloma . In AML, highly glycolytic AML blasts were more resistant to apoptosis induced by chemotherapeutic drugs ARTA (all‐ trans ‐retinoic acid) and/or ATO (arsenic trioxide) in vitro, suggesting potential resistance to induction chemotherapy .…”