Glucose metabolic phenotype of pancreatic cancer

Table 1 Systematic review of the literature involving glycolytic enzymes and pancreatic ductal adenocarcinoma

Glycolytic enzyme	In vitro studies		In vivo/clinical studies
	Ref.	Summary	Ref.	Summary
Hexokinase (HK)	[23-30,32,33,153-155]	Induced by hypoxia. Higher expression in PDAC than acinar cells. Suppresses mitochondrial ATP production	[31,153,156,157]	HK-2 expression suggests an unfavourable clinical outcome
Phosphoglucose isomerase (PGI)	[29,38-40,158]	Stimulates cell migration and metastatic potential. Induced by hypoxia. β-1 integrins are stimulated by PGI	[39]	Over-expression contributes to a more aggressive PDAC phenotype
Phosphofructokinase (PFK)	[11,48]	Upregulated in PDAC epithelia.
Aldolase	[49,52,54]	Overexpressed in PDAC. Induced by hypoxia. Delays apoptosis.	[52,53]	Highly expressed in PDAC where HIF-1α is constitutively expressed. Inhibition prolongs survival
Triosephosphate isomerase (TPI)	[55,56]	Overexpressed in PDAC
Glyceradehyde-3-Phosphate Dehydrogenase (G3PD)	[27,50,55,57,58,61,159]	Overexpressed in PDAC. Increases PDAC metabolic activity, and disrupts downstream apoptotic capases	[50,58]	Increased expression. Possible biomarker candidate.
Phosphoglycerate kinase (PK)	[62-66,160]	Overexpressed in PDAC. Angiogenesis promoter	[63]	No significant increase in expression in a murine model, but fivefold increase in activity.
Phosphoglycerate mutase (PGM)	[67,68]	M-isoform is under-expressed and B-isoform is over-expressed in murine models
Enolase	[55-58,69-83]	Overexpressed in PDAC. Promotes cell migration and metastasis. Biomarker candidate	[58,69,76,77,161-163]	Increased expression. Induced antibodies to enolase-alpha correlates to a better outcome
Pyruvate kinase (PK)	[108,109,117,121,122,157,164-166]	Overexpressed in PDAC. Dimeric form favours synthesis; Tetrameric form favours energy production; PK-M2 used as a tumour marker	[110,112,115,119,120,157,167,168]	M2 isoform levels correlate to tumour metastasis. HK-2 and M2 expression indicates an unfavourable clinical outcome
Lactate dehydrogenase (LDH)	[28,89,123-138,164,169-179]	Overexpressed in PDAC. Down regulated by graviola	[153,180-183]	Down regulated by graviola to reduce tumorigenicity and metastasis

HIF: Hypoxia-inducible factor; PDAC: Pancreatic ductal adenocarcinoma.

Table 2 Systematic review of the literature involving Krebs cycle enzymes and pancreatic ductal adenocarcinoma

Glycolytic Enzyme	In vitro/In vivo/clinical studies
	Ref.	Summary
Pyruvate dehydrogenase	[30,109,131,132,140,154,164,170,171,173,177,179,180,184-188]	Inhibition of pyruvate dehydrogenase kinase (the activity of which is regulated by pyruvate dehydrogenase) stimulates the Krebs cycle and reverses the Warburg effect.
Pyruvate carboxylase	[141]	Over expressed in human and murine PDAC
Citrate synthase	[67,124,179]	Over expressed in PDAC. Activity of citrate synthase also higher in PDAC compared to normal tissue
Aconitase	[67]	Mitochrondrial isoform under-expressed
Isocitrate dehydrogenase	[67,158,189,190]	Regulated by HuR (an RNA-binding protein) in PDAC.
a-ketoglutarate dehydrogenase	[67,187]	Marginally increased in murine PDAC
Succinyl-CoA synthetase	[67]	Reduced expression
Succinic dehydrogenase	[67,128]	Over expressed in human and murine PDAC
Fumarase	[30]	HIF-1α increases fumarate by inhibiting distal mitochondrial metabolisms
Malate dehydrogenase	[50,64,67]	Over expressed in human and murine PDAC. Possible candidate biomarker

HIF: Hypoxia-inducible factor; PDAC: Pancreatic ductal adenocarcinoma.

Table 3 Summary of changes in glycolysis in pancreatic ductal adenocarcinoma

Glycolytic enzyme	Encoding gene	Change in PDAC	Implicated pathways	Known inhibitors	Inhibitor effect in PDAC
Hexokinase			HIF	2-Deoxy-D-glucose
Hexokinase I	10q22	Up	mTor
Hexokinase II	2p13	Up	K-ras	3-BP[21]; Lonidamine, Everolimus	Reduced PDAC survival/induces PDAC necrosis
Hexokinase III	5q35.2	-	Akt
Glucokinase	7p15.3-p15.1
Phosphoglucose Isomerase (also known as Autocrine Motility Factor)	19q13.1	Up	HIF; Apoptosis	Insulin-like growth factor binding protein-3; Herceptin; 3-(5'-hydroxymethyl-2'-furyl)-1-benzyl indazole	Reduces overall cell viability and increases apoptosis rates
Phosphofructokinase			HIF	Aurintricarboxylic acid[191]	Inhibits fatty acid synthesis in rat hepatocytes
PFK-M (muscle type)	12q13.3	Down
PFK-L (liver type)	21q22.3	Up
PFK-P (platelet type)	10p15.3-p15.2	Up
Aldolase			HIF	3-fluro-D-glucose; 4-fluro-D-glucose
Aldolase-A	16p11.2	Up		3-[2-hydroxyethyl(methyl)amino]-2-quinoxalinecarbonitrile 1,4-dioxide	Reduces PDAC proliferation and tumour volume
Aldolase-B	5q22	Down
Aldolase-C	17cen-q12	Up
Triose Phosphate Isomerase	12p13	Up		2-phosphoglycolate; D-glycerol-1-phosphate[192]
Glyceraldehyde Phosphate Dehydrogenase			HIF; p53	Iodoacetate[27]; gossypol[21]	Reduces cell survival and induces necrosis. No effect on K-ras
GAPDHS	12p13	Up
GAPDHS (testes-specific)	19q13.12
Phosphoglycerate Kinase			HIF	1,3-bisphosphoglycerate[193]
PGK1	Xq13.3	Up
PGK2	6p12.3	?
Phosphoglycerate Mutase			p53	Inositol hexakisphosphate[194]
PGM-B	1p31	Up
PGM-M	4p14	Down
Enolase			c-Myc	Sodium fluoride[21]; D-tartonate; 3-aminoenolpyruvate 2-phosphate[195]
ENO1 (alpha)	1p36.2	Up
ENO2 (gamma, neuronal)	12.p13	Up
ENO3 (beta, muscle)	17pter-p11	-
Pyruvate Kinase			Tyrosine kinase
Isoform PK-M1 (liver/RBC)	1q21	-	Akt/c-Myc
Isoform PK-M2 (muscle)	15q22	Up		L-phospholactate; M2-PK-binding peptide aptamers[196]	Anti-cancer effects in animal models
Dimeric form
Tetrameric form

HIF: Hypoxia-inducible factor; PDAC: Pancreatic ductal adenocarcinoma.

Table 4 Summary of changes in anaerobic fermentation in pancreatic ductal adenocarcinoma

Glycolytic enzyme	Encoding gene	Change in PDAC	Implicated pathways	Known inhibitors	Inhibitor effect in PDAC
Lactate dehydrogenase				Oxamate	Inhibits PDAC growth
Lactate dehydrogenase A	11p15.4	Up	c-Myc; mTor	Aryl-substituted N-hydroxyindole-2-carboxylates; Everolimus (by blocking the mTor pathway[28])	Inhibits PDAC growth
Lactate dehydrogenase B	1p12.2-p12.1	Up
Lactate dehydrogenase C	11p15.1	-

PDAC: Pancreatic ductal adenocarcinoma.

Table 5 Summary of changes in aerobic respiration in pancreatic ductal adenocarcinoma

Glycolytic Enzyme	Encoding gene	Change in PDAC	Implicated pathways	Known inhibitors	Inhibitor effect in PDAC
Pyruvate dehydrogenase complex	11p13		HIF-1	Dichloroacetate (inhibits PDC regulator, pyruvate dehydrogenase kinase)	Stimulates Krebs Cycle and reverses Warburg effect; Reduces PDAC proliferation and viability
Pyruvate dehydrogenase				Stimulator: Lipoic acid	Reduces cancer cell viability
Pyruvate dehydrogenase α	Xp22.1	Down
Pyruvate dehydrogenase β	3p21.1-p14.2	Down
Pyruvate carboxylase	11q13.4-q13.5	Up/down1		Avidin
Citrate synthase	12q13.2	Up		Succinyl-CoA
Aconitase				Flouroacetate
Aconitase 1 (soluble)	9p21.1
Aconitase 2 (mitochondrial)	22q13.2	Down
Isocitrate dehydrogenase
ICD (soluble)	2q33.3
ICD (mitochondrial)	15q26.1	Down
Oxoglurate (α-ketoglutarate) Dehydrogenase	7p14-p13	Up
Succinyl-CoA synthetase		Down
Succinic dehydrogenase		Up/down1
Fumarase	1q42.1			D-malic, trans-aconitic, citrate, glycine
Malate dehydrogenase
MD (soluble)	2p13.3
MD (mitochondrial)	7cen-q22	Up

¹Under-expressed in animal PDAC. PDAC: Pancreatic ductal adenocarcinoma.