Tingyu Liu

Akt-dependent glucose metabolism promotes Mcl-1 synthesis to maintain cell survival and resistance to Bcl-2 inhibition.

Most cancer cells utilize aerobic glycolysis, and activation of the phosphoinositide 3-kinase/Akt/mTOR pathway can promote this metabolic program to render cells glucose dependent. Although manipulation of glucose metabolism may provide a means to specifically eliminate cancer cells, mechanistic links between cell metabolism and apoptosis remain poorly understood. Here, we examined the role and metabolic regulation of the antiapoptotic Bcl-2 family protein Mcl-1 in cell death upon inhibition of Akt-induced aerobic glycolysis. In the presence of adequate glucose, activated Akt prevented the loss of Mcl-1 expression and protected cells from growth factor deprivation-induced apoptosis. Mcl-1 associated with and inhibited the proapoptotic Bcl-2 family protein Bim, contributing to cell survival. However, suppression of glucose metabolism led to induction of Bim, decreased expression of Mcl-1, and apoptosis. The proapoptotic Bcl-2/Bcl-xL/Bcl-w inhibitor, ABT-737, shows clinical promise, but Mcl-1 upregulation can promote resistance. Importantly, inhibition of glucose metabolism or mTORC1 overcame Mcl-1-mediated resistance in diffuse large B cell leukemic cells. Together these data show that Mcl-1 protein synthesis is tightly controlled by metabolism and that manipulation of glucose metabolism may provide a mechanism to suppress Mcl-1 expression and sensitize cancer cells to apoptosis.

MiR-215 Is Induced Post-transcriptionally via HIF-Drosha Complex and Mediates Glioma-Initiating Cell Adaptation to Hypoxia by Targeting KDM1B.

The hypoxic tumor microenvironment serves as a niche for maintaining the glioma-initiating cells (GICs) that are critical for glioblastoma (GBM) occurrence and recurrence. Here, we report that hypoxia-induced miR-215 is vital for reprograming GICs to fit the hypoxic microenvironment via suppressing the expression of an epigenetic regulator KDM1B and modulating activities of multiple pathways. Interestingly, biogenesis of miR-215 and several miRNAs is accelerated post-transcriptionally by hypoxia-inducible factors (HIFs) through HIF-Drosha interaction. Moreover, miR-215 expression correlates inversely with KDM1B while correlating positively with HIF1α and GBM progression in patients. These findings reveal a direct role of HIF in regulating miRNA biogenesis and consequently activating the miR-215-KDM1B-mediated signaling required for GIC adaptation to hypoxia.

Glycolysis-dependent histone deacetylase 4 degradation regulates inflammatory cytokine production

In prolonged activated microglia, GSK3b-iNOS-NO–dependent glycolysis activates HDAC4 degradation, which results in attenuation of inflammatory cytokine. Glycolysis is not only required for immune cell activation but is also involved in its termination by triggering HDAC4 degradation.

Glucose transporter 1-mediated glucose uptake is limiting for B-cell acute lymphoblastic leukemia anabolic metabolism and resistance to apoptosis

The metabolic profiles of cancer cells have long been acknowledged to be altered and to provide new therapeutic opportunities. In particular, a wide range of both solid and liquid tumors use aerobic glycolysis to supply energy and support cell growth. This metabolic program leads to high rates of glucose consumption through glycolysis with secretion of lactate even in the presence of oxygen. Identifying the limiting events in aerobic glycolysis and the response of cancer cells to metabolic inhibition is now essential to exploit this potential metabolic dependency. Here, we examine the role of glucose uptake and the glucose transporter Glut1 in the metabolism and metabolic stress response of BCR-Abl+ B-cell acute lymphoblastic leukemia cells (B-ALL). B-ALL cells were highly glycolytic and primary human B-ALL samples were dependent on glycolysis. We show B-ALL cells express multiple glucose transporters and conditional genetic deletion of Glut1 led to a partial loss of glucose uptake. This reduced glucose transport capacity, however, was sufficient to metabolically reprogram B-ALL cells to decrease anabolic and increase catabolic flux. Cell proliferation decreased and a limited degree of apoptosis was also observed. Importantly, Glut1-deficient B-ALL cells failed to accumulate in vivo and leukemic progression was suppressed by Glut1 deletion. Similarly, pharmacologic inhibition of aerobic glycolysis with moderate doses of 2-deoxyglucose (2-DG) slowed B-ALL cell proliferation, but extensive apoptosis only occurred at high doses. Nevertheless, 2-DG induced the pro-apoptotic protein Bim and sensitized B-ALL cells to the tyrosine kinase inhibitor Dasatinib in vivo. Together, these data show that despite expression of multiple glucose transporters, B-ALL cells are reliant on Glut1 to maintain aerobic glycolysis and anabolic metabolism. Further, partial inhibition of glucose metabolism is sufficient to sensitize cancer cells to specifically targeted therapies, suggesting inhibition of aerobic glycolysis as a plausible adjuvant approach for B-ALL therapies.

Abstract C155: Targeting glucose metabolism to suppress Ph+B-ALL progression.

Philadelphia chromosome positive B cell derived acute lymphoblastic leukemia (Ph+B-ALL) is a type of aggressive leukemia that lacks effective treatment. The high glucose metabolism observed in many other cancers suggests that targeting glucose metabolism may provide a novel therapeutic approach for Ph+B-ALL. However, metabolic features of Ph+B-ALL and metabolic stress responses have not been described. In this study, we examined human primary B-ALL samples, B-ALL cell lines and primary murine Ph+B-ALL to identify metabolic program and metabolic stress responses of Ph+B-ALL cells. Metabolic measurements of extracellular flux and glucose consumption showed that B-ALL cell lines are highly glycolytic and preferentially utilize glucose. Consistent with a dependence on elevated glycolysis, primary human B-ALL cells were more sensitive than normal B cells to inhibition of glycolysis with 2-deoxyglucose (2-DG). This metabolic stress induced cell death was likely to be mediated through p53 and Bcl-2 family proteins. 2-DG treatment induced expression of pro-apoptotic Bcl-2 family protein Bim and primary murine Ph+B-ALL cells generated from p53-/- or Bim-/- background remained viable even when treated with 2-DG. To specifically investigate how inhibition of glucose metabolism impacts B-ALL survival and disease progression in vivo with genetic tools, we generated murine Ph+ B-ALL cells on a Glut1fl/fl Ubi-CreER background that allow specific deletion of Glut1 in cancer cells upon treatment of tamoxifen. In vitro deletion of Glut1 reduced glucose uptake and glucose metabolism, although glycolysis was not wholly suppressed. This partial reduction of glucose metabolism led to greatly reduced cell proliferation and some cell death in vitro. Importantly, in vivo deletion of Glut1 after transfer of B-ALL cells into congenic recipients suppressed B-ALL progression and prolonged animal survival. These data show that B-ALL cells exhibit high glucose metabolism similar to other types of cancer and are sensitive to glucose metabolism inhibition. Reduction of glucose metabolism can impede B-ALL proliferation or cause cell death through p53 and Bim and thus suppress B-ALL progression in vivo. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):C155. Citation Format: Tingyu Liu, Handan Xiang, Amanda Nichols, Valerie Gerriets, Rigel Kishton, David Rizzieri, Jeffrey C. Rathmell. Targeting glucose metabolism to suppress Ph+B-ALL progression. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr C155.