PKM2 activation sensitizes cancer cells to growth inhibition by 2-deoxy-D-glucose

Tee, Sui Seng; Park, Jae Mo; Hurd, Ralph E.; Brimacombe, Kyle R.; Boxer, Matthew B.; Massoud, Tarik F.; Rutt, Brian K.; Spielman, Daniel M.

doi:10.18632/oncotarget.19630

Cited by 17 publications

(14 citation statements)

References 50 publications

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“…Combination treatment resulted in reduced viability of a range of cell lines in standard cell culture conditions. 41) Moreover, 2-deoxy-D-glucose competitively inhibited the production of G6P from glucose, which resembles that of PA. This study supported the beneficial effects of dual targeting of PA to PKM2 and HK2.…”

Section: Discussionmentioning

confidence: 87%

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Targeting Pyruvate Kinase M2 and Hexokinase II, Pachymic Acid Impairs Glucose Metabolism and Induces Mitochondrial Apoptosis

Miao

Han

Zhang

et al. 2019

Biological & Pharmaceutical Bulletin

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Pachymic acid (PA), a triterpenoid from Poria cocos, has various pharmacological effects, including anti-inflammatory, anti-cancer, anti-aging, and insulin-like properties. PA has gained considerable research attention, but the mechanism of its anti-cancer effects remains unclear. In this study, pyruvate kinase M2 (PKM2) was discovered as a PA target via the drug affinity responsive target stability. Molecular docking and enzyme assay revealed that PA is a competing activator of PKM2, and mimics the natural activator, fructose-1,6-bisphosphate. PKM2 activation should augment the flux of glycolysis. However, decreased glucose uptake and lactate production after PA treatment was observed in SK-BR-3 breast carcinoma cells, indicating a blockage or downregulation of glycolysis. The potential of previously reported triterpenoids in blocking hexokinase II (HK2) activity inspired us to investigate the inhibition effect of PA on HK2 activity. Molecular docking and enzyme assay confirmed that PA was an inhibitor of HK2, with an IC 50 of 5.01 µM. The possible consequences of glycometabolic regulation by PA, such as dissociation of HK2 from the mitochondria, release of mitochondrial cytochrome (Cyt) c, depletion of ATP, and generation of reactive oxygen species, were further validated. Furthermore, the details of the possible linkage of targeting PKM2 and HK2 with previously reported actions of PA were discussed. The results of our study provided valuable information on the anti-cancer mechanisms of PA.

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Section: Discussionmentioning

confidence: 87%

“…9) Moreover, ROS-mediated ER stress is associated with apoptosis initiation, which has been observed in PAtreated lung cancer cells. 4,40) In summary, ROS generation by PA may be a fundamental mechanism for the anti-cancer activity of PA.…”

Section: Discussionmentioning

confidence: 99%

Targeting Pyruvate Kinase M2 and Hexokinase II, Pachymic Acid Impairs Glucose Metabolism and Induces Mitochondrial Apoptosis

Miao

Han

Zhang

et al. 2019

Biological & Pharmaceutical Bulletin

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“…In a study with pancreatic cancer cells, the inhibition of PKM2 expression in the normal glucose medium did not affect cell growth and proliferation, whereas the suppression of PKM2 expression in low glucose (0.5mM) medium increased cell viability 18 . In another study with lung cancer cells, it was determined that induced PKM2 mRNA expression in low glucose medium increased cell proliferation 19 . In our study, we found that PKM2 expressions decreased significantly in low glucose medium in all cell lines we used.…”

Section: Discussionmentioning

confidence: 99%

Expression of Genes Involved in Glycolytic Pathway Upon Glucose Limitation in Leukemia Cells

Yücel¹,

Kara²,

Ada³

et al. 2019

MMJ

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Objective: Leukemia is the cancer of hematopoietic system and is characterized by abnormal proliferation of blood precursor cells. Leukemia cells as other cancer cells multiply rapidly and they have increased nutrient needs. The most commonly used nutrient by cancer cells is glucose and therefore it is hypothesized that glucose is present at a low level in the microenvironment of cancer cells. Metabolic changes in leukemia cells due to nutrient deficiency add extra liabilities to the cells. In recent studies, increased glycolysis and reprogrammed glucose metabolism have been shown in different tumors Intermediate steps of glycolysis involving hexokinase, phosphofructokinase, pyruvate dehydrogenase kinase and lactate dehydrogenase enzymes are rate-limiting steps in the reaction and increased expressions were correlated with poor prognosis of leukemia.The aim of this study is to investigate the expression of glycolytic genes in low glucose conditions. Method: In this study, we control expression of rate-limiting glycolytic enzymes' mRNA expressions in K562, NB-4 and HL-60 cell lines in low glucose (1 mM) concentration compared to normal (10 mM) concentration using qRT-PCR assay. Results: We found that PKM2 and LDHA mRNA expressions were significantly decreased in low glucose conditions. On the other hand, HK1 and HK2 expressions were increased in K562 cells (p<0.001). We also found that PFKL expression was decreased in K562 cells. Conclusion: Our results show that targeting glucose metabolism can reduce expression of glycolytic genes and therefore in compliance with the literature suggest that glucose metabolism may be a target in the treatment of leukemia.

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“…Four recent reports have investigated the Lac/Pyr ratio (or k PL ). Ravoori et al and Tee et al found that this ratio increases, whereas Park et al and Iversen et al found it to remain stable, when a variety of preclinical tumours (glioma, mammary carcinoma, ovarian, lung carcinoma) respond to therapy. In References 33, 35 and 36, the therapeutic agent used displayed anti‐angiogenic or vascular disrupting activity, while in Reference the drug used was an activator of PKM2.…”

Section: Mrs(i)‐detectable Metabolic Hallmarks Of Cancer: Applicationmentioning

confidence: 99%

“…Ravoori et al and Tee et al found that this ratio increases, whereas Park et al and Iversen et al found it to remain stable, when a variety of preclinical tumours (glioma, mammary carcinoma, ovarian, lung carcinoma) respond to therapy. In References 33, 35 and 36, the therapeutic agent used displayed anti‐angiogenic or vascular disrupting activity, while in Reference the drug used was an activator of PKM2. The rationale to explain this initially conflicting evidence is essentially put forward in References 33 and 36: anti‐angiogenic agents will produce hypoxic regions in the tumour, causing increased glycolytic flow to maintain required ATP (adenosine triphosphate) production by the tumour cell, overriding the decreased demand of carbon precursors for cell duplication by the growth‐arrested tumour cells.…”

Section: Mrs(i)‐detectable Metabolic Hallmarks Of Cancer: Applicationmentioning

confidence: 99%

Cancer metabolism in a snapshot: MRS(I)

2019

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The contribution of MRS(I) to the in vivo evaluation of cancer-metabolism-derived metrics, mostly since 2016, is reviewed here. Increased carbon consumption by tumour cells, which are highly glycolytic, is now being sampled by 13 C magnetic resonance spectroscopic imaging (MRSI) following the injection of hyperpolarized [1-13 C] pyruvate (Pyr). Hot-spots of, mostly, increased lactate dehydrogenase activity or flow between Pyr and lactate (Lac) have been seen with cancer progression in prostate (preclinical and in humans), brain and pancreas (both preclinical) tumours. Therapy response is usually signalled by decreased Lac/Pyr 13 C-labelled ratio with respect to untreated or nonresponding tumour. For therapeutic agents inducing tumour hypoxia, the 13 C-labelled Lac/bicarbonate ratio may be a better metric than the Lac/Pyr ratio. 31 P MRSI may sample intracellular pH changes from brain tumours (acidification upon antiangiogenic treatment, basification at fast proliferation and relapse). The steady state tumour metabolome pattern is still in use for cancer evaluation. Metrics used for this range from quantification of single oncometabolites (such as 2-hydroxyglutarate in mutant IDH1 glial brain tumours) to selected metabolite ratios (such as total choline to N-acetylaspartate (plain ratio or CNI index)) or the whole 1 H MRSI(I) pattern through pattern recognition analysis. These approaches have been applied to address different questions such as tumour subtype definition, following/predicting the response to therapy or defining better resection or radiosurgery limits. KEYWORDSanimal model study, cancer, cellular and molecular cancer imaging, hyperpolarized C-13, MRS and MRSI methods, phosphorus MRS/MRSI | TEMPORAL AND THEMATIC BOUNDARIES OF THE TOPICS COVEREDThe authors of this review declare at the outset that there is no intention of being exhaustive or systematic. The temporal boundaries reviewed will be modest: only relevant literature since 2016, chosen according to our bias. Earlier work or reviews will only be referred to in order to put recent findings in due perspective. Authors hope that this summary will give readers a picture of how far cancer metabolism analysis with MRS(I) has advanced and, perhaps, why it is not advancing further.For quite a long time MRS, rather than MRI, has been the only approach able to evaluate cancer metabolism. Nevertheless, the MRI-derived information related to cancer metabolism should not be forgotten: consider for example the chemical exchange saturation transfer (CEST) effect caused by exchangeable protons in water-derived images of glucose uptake and metabolism in tumours. 1,2 However, apart from these CESTrelated studies, we should acknowledge that most information about cancer metabolism using MR still refers to MRS(I) acquisitions, which are the ones dealt with in our text.Supplementary Figure 1 shows a PUBMED search illustrating the different proportions of articles investigating several cancer types through MRS(I) approaches. The retrieved information can help unders...

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PKM2 activation sensitizes cancer cells to growth inhibition by 2-deoxy-D-glucose

Cited by 17 publications

References 50 publications

Targeting Pyruvate Kinase M2 and Hexokinase II, Pachymic Acid Impairs Glucose Metabolism and Induces Mitochondrial Apoptosis

Targeting Pyruvate Kinase M2 and Hexokinase II, Pachymic Acid Impairs Glucose Metabolism and Induces Mitochondrial Apoptosis

Expression of Genes Involved in Glycolytic Pathway Upon Glucose Limitation in Leukemia Cells

Cancer metabolism in a snapshot: MRS(I)

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