Role of abnormal lipid metabolism in development, progression, diagnosis and therapy of pancreatic cancer

Table 1 Overexpression of lipogenic enzymes in human tumors

Enzyme name	Neoplasm type	Experimental model	Ref.
Fatty acid synthase (FASN)	Pancreatic cancer	Human tumor tissue, cell line	[96,104,105]
	Breast carcinoma	Human tumor tissue	[5,9,166]
	Prostate cancer	Human tumor tissue	[167]
	Melanoma	Human tumor tissue	[168]
	Nephroblastoma	Human tumor tissue	[169]
	Renal cancer	Cell line	[170]
	Endometrial carcinoma	Human tumor tissue	[12,171]
	Colon cancer	Human tumor tissue	[11,172]
	Ovarian neoplasms squamous cell	Human tumor tissue	[10,173]
	Carcinoma of the lung head and neck squamous	Human tumor tissue	[174]
	Cell carcinoma squamous cell	Human tumor tissue	[175]
	Carcinoma of the tongue	Human tumor tissue	[176]
ATP citrate lyase (ACLY)	Small cell lung cancer	Cell line	[251]
	Bladder cancer	Human tumor tissue	[7]
	Breast cancer	Cell line	[252]
	Gastric cancer	Human tumor tissue, cell line	[253]
	Colon cancer	Human tumor tissue	[254]
	Prostate cancer	Human tumor tissue	[254]
	Hepatocellular carcinoma	Human tumor tissue	[255]
Acetyl-CoA carboxylase (ACCA)	Prostate cancer	Human tumor tissue	[6]
	Hepatocellular carcinoma	Human tumor tissue	[255]
	Breast carcinoma	Human tumor tissue	[256]
Stearoyl-CoA desaturase (SCD1)	Pancreatic cancer	SCD1 indices in patients serum	[128]
	Clear cell renal cell carcinoma	Human tumor tissue	[200]
Acetyl-CoA synthetase (ACS)	Colon adenocarcinoma	Human tumor tissue	[257]
	Malignant glioma	Cell line	[258]
Citrate synthase (CS)	Pancreatic cancer	Human tumor tissue	[19]
	Renal cell carcinoma	Human tumor tissue	[20]

Table 2 Oncogenes and tumor suppressor genes, whose products participate in regulation of cancer cells metabolism

Oncogene/tumor suppressor	Metabolic pathway	Enzyme	Ref.
MYC	Glucose transport	GLUT1	[53-55]
	Glycolysis	Hexokinase 2
		Phosphohexose isomerase
		Phosphofructokinase 1
		Aldolase A
		3-phosphoglyceraldehyde dehydrogenase
		Phosphoglycerate kinase
		Phosphoglycerate mutase
		Enolase 1
		Pyruvate kinase 2
		Lactate dehydrogenase A
	Regulation of PDH	Pyruvate dehydrogenase kinase 1
	Glutamine transport	Glutamine transporters ASCT2 and SN2
	Glutaminolysis	Glutaminase 1
	Serine hydroxymethyltransferase
	Pyrimidine synthesis
	Aminoacids metabolism	CAD
		Ornithine decarboxylase
	Lipogenesis	Fatty acid synthase
p53	Glucose transport	GLUT1	[51,56-60]
	Glycolysis	Hexokinase 2
		Fructose-2,6-bisphosphatase
		Phosphoglycerate mutase
	Oxidative phosphorylation	Cyrochrome c oxidase
	Glutaminolysis	Glutaminase 2
	Pentose Phosphate Pathway	Glucose-6-phosphate dehydrogenase
	Regulation of PDH	Pyruvate dehydrogenase kinase 1
	Krebs cycle	Aconitase
KRAS	Glucose transport	GLUT1	[61,73,94]
	Glycolysis	Hexokinase 2
		Phosphofructokinase 1
		Lactate dehydrogenase A
	Pentose phosphate pathway	Transketolase
	Hexosamine synthesis	Phosphohexose aminotransferase
	Glutaminolysis	Glutamate dehydrogenase
		Aspartate transaminase
Akt/PTEN	Glucose transport	GLUT1	[50,113-115]
	Lipogenesis	FASN

Table 3 Oncogenes and tumor suppressor genes whose products alter the metabolism of pancreatic cancer cells

Gene	Protein	Mechanism of alteration in PDAC	Regulated processes in PDAC	Alteration in PDAC	Ref.
Oncogenes
KRAS	KRAS	Point mutations	Cell proliferation and survival, motility, glucose transport, glycolysis, hexosamine synthesis, nonoxidative pentose phosphate pathway arm, glutaminolysis	> 95%	[73,94,259-261]
AKT	AKT	Mutations, amplification	Signal transduction, lipogenesis, glucose transport	10%-20%	[73,79-81,262-264]
c-erbB2	HER2	Overexpression amplification	Proliferation, differentiation, survival	20%-80%	[265-268]
Myc	MYC	Amplification overexpression	Glycolysis, glutaminolysis, PDH inhibition	70%	[55,73,82,94,269]
Tumor suppressor genes
TP53	p53	Mutation and second allele deletion	Cell cycle, apoptosis, DNA repair, glucose transport, glycolysis, lipogenesis, ppp oxidative arm, glutaminolysis	50%-80%	[270-273]
Smad4/DPC4	SMAD4	Homozygous deletion, mutation and second allele deletion	Cell cycle, TGF-β signaling	55%	[274-276]
STK/LKB1	LKB1	Homozygous deletion, mutation and second allele deletion	Apoptosis, lipogenesis, energy production, protein synthesis	5%	[277-279]
CDKN2A/p16	p16	Homozygous deletion, mutation, hypermethylation	Cell cycle	95%	[280-282]
PTEN	PTEN	Hypermethylation, inhibition by miRNA	PI3K/AKT signaling pathway	30%-70%	[79,283,284]

PDAC: Pancreatic ductal adenocarcinoma.

Table 4 Most common genetic alterations observed in different types of human pancreatic cancers

Type of pancreatic cancer	Gene affected	Ref.
Pancreatic ductal adenocarcinoma (PDAC)	KRAS, AKT, MYC, TP53, SMAD4, CDKN2A, PTEN	[55,63,64,73,78,79,94,269,284-287]
(90% of all pancreatic cancers)
Acinar cell carcinoma (ACCA)	APC/β-catenin (CTNNB1), BRCA2, BCL10	[288-290]
(< 1% of all pancreatic cancers)
Adenosquamous carcinoma (ASC)	TP53, CDKN2A, KRAS, E-cadherin,	[291,292]
(< 1% of all pancreatic cancers)
Intraductal papillary mucinous neoplasm (IPNM)	GNAS, KRAS, RNF4, STK11/LKB1, MUC1, MUC2, hTERT, COX2, Shh	[278,293,294]
(1%-3% of all pancreatic cancers)
Mucinous cystic neoplasm (MCN)	KRAS, RNF4, TP53, CDKN2A	[295]
(< 1% of all pancreatic cancers)
Serous cystadenoma (SCN)	VHL	[296]
(< 1% of all pancreatic cancers)
Solid-pseudopapillary neoplasm (SPN)	APC/β-catenin (CTNNB1), E-cadherin	[297,298]
(1%-2% of all pancreatic cancers)
Pancreatic neuroendocrine tumors (PanNET)	DAXX, ATRX, MEN1, TSC2, PTEN, PI3KCA, CHGA, CHGB, mTOR	[299-302]
(2%-5% of all pancreatic cancers)

Table 5 Lipogenic enzyme inhibitors that can be used as potential antitumor drugs

Enzyme name	Inhibitor	Type of neoplasm	Ref.
Fatty acid synthase (FASN)	Cerulenin	Breast cancer,	[303]
		ovarian cancer	[304]
	C75	Breast cancer	[216]
		Pancreatic cancer	[232]
	Epigallocatechin-3-gallate (EGG)	Prostate cancer	[228]
	C93	Lung cancer	[305]
		Ovarian cancer	[306]
	Luteolin	Breast cancer, ovarian cancer	[228]
		Pancreatic cancer	[232]
	Orlistat	Prostate cancer	[307]
ATP citrate lyase (ACLY)	SB-204990 hydroxycitrate	Lung cancer	[308]
		Brest cancer	[18]
		Pancreatic cancer	[101]
Acetyl-CoA carboxylase (ACCA)	Soraphen A TOFA	Prostate cancer	[309]
		Lung cancer, colon cancer	[310]
Stearoyl-CoA desaturase (SCD1)	CVT-11127 TOFA	Lung cancer	[222]
		Colon cancer	[225]
Acetyl-CoA synthetase (ACS)	Triacsin c	Various cancers cell lines	[311]