Bioenergetic alteration in gastrointestinal cancers: The good, the bad and the ugly

Table 1 Genetic and epigenetic alterations in hypoxia-related enzymes correlated with the development and progression of gastrointestinal cancers

Cancer type	Gene	Type of change	Consequence	Model	Ref.
HCC and CCA	PHD2	Haplo-deficiency	Stabilized HIF-1 and promoted carcinogenesis and progression of HCC/CCA	Mice	[66,67]
HCC	PHD3	Reduced tumor level	Correlated with elevated levels of HIF-1, aggressive tumor behavior, and a poor prognosis in HCC patients	HCC patient	[68]
GC	PHD3	Reduced tumor level	Correlated negatively with tumor size and stage, as well as HIF-1 and VEGF expression	GC patient	[69,70]
GC	PHD2	Reduced tumor level	Correlated with shortened overall survival	GC patient	[71]
CRC	PHD1-3	Reduced tumor level	Although not correlated with HIF-1 expression, PHD2 was the only factor found to be associated with unfavorable overall survival	CRC patient	[72]
PAC	PHD1-3	Increased tumor level	PHD1-3 expression was elevated, and specifically PHD3 expression was found to be associated with unfavorable overall disease-specific survival	PAC patient	[73]
PAC	VHL	Promoter methylation or deletion of VHL	Correlated with decreased VHL expression and poor prognosis	PAC patient	[74]
CRC	VHL	VHL mutation	Elevated cytoplasmic expression of HIF-1 in tumors	CRC patient	[75]
HCC	VHL	Reduced tumor level	Negative VHL expression was correlated with an unfavorable prognosis	HCC patient	[76]

ESCA: Esophageal cancer; GC: Gastric cancer; HCC: Hepatocellular carcinoma; CCA: Cholangiocarcinoma; PAC: Pancreatic cancer; CRC: Colorectal cancer; PHD: Prolyl hydroxylase; VHL: Von Hippel-Lindau tumor suppressor.

Table 2 Defects in cytochrome c oxidase subunits correlated with bioenergetic alterations and the growth or progression of gastrointestinal cancers

Type	Gene	Type of defect	Consequence	Model	Ref.
GC	Full COX complex	Increased expression	Correlated with poor prognosis	GC patient	[83]
CRC	Full COX complex	Increased expression	May be involved in the initiation of carcinogenesis, but not in cancer progression	CRC patient	[84]
ESCA	MTCO1	Increased expression	There is no correlation with clinical variables or survival	ESCA patient	[86]
GC	MTCO1	Increased expression	Correlated with gastric tumorigenesis, de-differentiation, and distant metastasis, but showed no significant correlation with prognosis	GC patient	[87,88]
HCC	MTCO1	Reduced expression	Correlated with postoperative prognosis	HCC patient	[89]
CCA	MTCO1	Reduced expression	Reduced MTCO1 correlates with increased VDAC1 expression but not with other clinicopathological factors	CCA patient	[90]
HCC	MTCO3	Increased expression	HBx interacted with MTCO3, leading to an increase in MTCO3 expression levels and an enhancement in OXPHOS activity	Cell line	[91,92]
CRC	MTCO1	Genetic variation	The Gly125Asp substitution in MTCO1 correlated with an increased risk of CRC and caused proton leak in COX	CRC patient	[93,94]
GC	MTCO3	Genetic variation	Polymorphisms at mtDNA positions 9540 and 9548 correlated with an increased risk of GC	GC patient	[95]
HCC	MTCO3	Genetic variation	Polymorphisms at mtDNA position 9545 correlated with an increased risk of HCC	HCC patient	[96]
ESCA	COX4I1	Expression silenced	Promotes alterations in cellular bioenergetics and increases cancer cell aggressiveness	ESCA Cell line	[99]
ESCA	COX5B	Expression silenced	Promotes alterations in cellular bioenergetics and increases cancer cell aggressiveness	ESCA Cell line	[99]
HCC	COX5B	Increased in tumor	Correlated with prognosis, regulated bioenergetic alterations, and influenced cell proliferation, tumor growth, and migration	HCC patient, cell line, mouse model	[100]
CRC	COX5B	Reduced in tumor	Correlated with prognosis, modulated COX activity, and controlled cell proliferation, apoptosis, and response to chemotherapy	CRC patient and cell line	[101,102]
CRC	COX4I2	Increased in tumor	Promoted cell proliferation, migration, tumorigenesis, and angiogenesis	CRC patient and cell line	[103]
PAC	COX6C	Increased expression	Modulated COX activity and cell proliferation	PAC cell line	[104]
PAC	COX6B2	Increased in tumor	Correlated with prognosis, and modulated cancer cell metastatic potential, and altered bioenergetic homeostasis	PCA patient and cell line	[105]

COX: Cytochrome c oxidase; GI: Gastrointestinal; ESCA: Esophageal cancer; GC: Gastric cancer; HCC: Hepatocellular carcinoma; CCA: Cholangiocarcinoma; PAC: Pancreatic cancer; CRC: Colorectal cancer; MTCO1: Mitochondrially encoded cytochrome c oxidase I; MTCO2: Mitochondrially encoded cytochrome c oxidase II; MTCO3: Mitochondrially encoded cytochrome c oxidase III; COX4I1: Cytochrome c oxidase subunit 4I1; COX4I2: Cytochrome c oxidase subunit 4I2; COX5B: Cytochrome c oxidase subunit 5B; COX6C: Cytochrome c oxidase subunit 6C; COX6B2: Cytochrome c oxidase subunit 6B2.

Table 3 Implications of defects in adenosine triphosphate synthase subunits on bioenergetic alterations and the development or progression of gastrointestinal cancer

Type	Gene	Type of defect	Consequence	Model	Ref.
GC	ATP5F1B	Increased in tumor	Higher ATP5B expression correlated with poor prognosis. Over-expression of ATP5F1B increased intracellular and extracellular ATP levels, cell proliferation, migration, and invasion	GC patient, cell line, and xeno-transplantation mouse model	[107]
GC	ATP5F1B	Reduced in tumor	Reduced ATP5F1B expression correlated with elevated glycolytic enzyme levels	GC patient	[108]
HCC	ATP5F1B	Reduced in tumor	Reduced ATP5F1B expression correlated with impaired OXPHOS	HCC patient	[109,110]
ESCA	ATP5F1B	Reduced in tumor	Reduced ATP5F1B expression correlated with elevated glycolytic enzyme levels	ESCA patient	[108]
CRC	ATP5F1B	Reduced in tumor	Reduced ATP5F1B expression correlated with poor prognosis in CRC patients	CRC patient	[109]
PAC	ATP5F1B	Reduced in tumor	Unknown	PAC patient and cell line	[111]
CRC	ATP5F1A	Increased in liver metastasized tumor	Silencing of ATP5F1A inhibited cell invasion and reduced cell proliferation in CRC cancer cells	CRC patient and cell line	[112]
CRC	ATP5F1E	Increased in tumor	Higher ATP5E levels correlated with poor prognosis. Silencing of ATP5F1E inhibited cancer cell migration and invasion in vitro, and distal metastasis in vivo	CRC patient, cell line, and tail vein injected mouse model	[113]
CRC	ATP5F1D	Increased in liver metastasized tumor	Higher ATP5F1D expression correlated with poor prognosis, and silencing of ATP5F1D inhibited cell invasion	CRC patient and cell line	[112]

ATP: Adenosine triphosphate; GI: Gastrointestinal; ESCA: Esophageal cancer; GC: Gastric cancer; HCC: Hepatocellular carcinoma; CCA: Cholangiocarcinoma; PAC: Pancreatic cancer; CRC: Colorectal cancer; ATP5F1A: ATP synthase F1 subunit alpha; ATP5F1B: ATP synthase F1 subunit beta; ATP5F1D: ATP synthase F1 subunit delta; ATP5F1E: ATP synthase F1 subunit epsilon.

Table 4 Promising novel bioenergetics targeting drugs for gastrointestinal cancer therapy

Inhibitor	Target	GI model	Consequence	Clinical trial	Ref.
Targeting glucose transportation
Genistein	HIF1A, GLUT1 and HK2	GC, ESCA, HCC, CCA, PCA, and CRC cell lines	Inhibited cancer cell proliferation, cell cycle progression, migration, invasion, angiogenesis, stemness, spheroid formation, EMT, and promoted apoptosis	CRC patient, phase I/II (NCT10985763), and PAC patient, phase I/II (NCT02336087, NCT00376948 and NCT00882765)	[131-140]
Apigenin	HIF1A, GLUT1 and HK2	GC, ESCA, HCC, CCA, PCA, and CRC cell lines	Inhibited cancer cell proliferation, colony-forming, cell cycle progression, migration, invasion, angiogenesis, and induced apoptosis	CRC patient, phase II (NCT00609310)	[141-146]
WZB117	GLUT1	HCC, CCA, PAC, and CRC cell lines, and xenograft models	Reduced glucose uptake, inhibits cell proliferation, and invasion, and enhanced chemosensitivity	None in GI cancers	[148-151]
STF-31	GLUT1	PAC and CRC cell lines, and xenograft model	Reduced cancer stem cell properties, such as stemness, and inhibits cell proliferation, viability, and tumor growth	None in GI cancers	[152,153]
BAY-876	GLUT1	ESCA, PCA, and CRC cell lines, and xenograft mouse models	Reduced cancer cell proliferation, tumor growth, and glucose uptake, while also increased chemosensitivity	None in GI cancers	[154-156]
Targeting glucose metabolism
2-Deoxy-D-glucose (2-DG)	HK2	GC, ESCA, HCC, PAC and CRC cell lines, xenograft models, and rat HCC and hamster PAC models	Inhibited cell proliferation, tumor growth, and promoted chemosensitivity	PAC patient, phase I (NCT00096707)	[159-165]
3-Bromopyruvate (3-BrPA)	HK2	GC, HCC, PCA, and CRC cell lines, and rabbit, transgenic mouse and xenograft mouse models	Inhibited cellular ATP generation, cell proliferation, and tumor growth. Also induced mitochondrial depolarization, reduced animal serum VEGF levels, and promoted cell death and chemosensitivity	HCC patient, case report[170]	[167-170]
Lonidamine (LND)	HK2	HCC, CCA, and CRC cell lines, hamster CCA model, and GC and CRC patients	Inhibited cell proliferation, migration, invasion, and cell cycle progression. Increased chemosensitivity, patient overall response rate, and duration of disease progression in GC patients. However, was ineffective and toxic in advanced CRC patients	GC patient, phase II[172], CRC patients, phase II[176,177]	[174-179]
3-(3-pyridinyl)-1-(4-pyridinyl)-2-propen-1-one (3PO)	PFKFB3	HCC, PAC, and CRC cell lines, and transgenic and xenograft mouse models	Inhibited glucose uptake, cell proliferation, tumor growth, angiogenesis, fibrogenesis, and promoted cell death	None in GI cancers	[182-184]
1-(4-pyridinyl)-3-(2-quinolinyl)-2-propen-1-one (PFK15)	PFKFB3	GC, HCC, PAC, and CRC cell lines, xenograft models, and HCC rat model	Inhibited cell proliferation, migration, invasion, cell cycle progression, tumor growth, and enhanced cell death	None in GI cancers	[185-189]
1-pyridin-4-yl-3-[7-(trifluoromethyl)-quinolin-2-yl]-prop-2-en-1-one (PFK158)	PFKFB3	None in GI cancers	None in GI cancers	Solid tumor patients, phase I (NCT02044861)	[190]
Shikonin	PKM2	GC, ESCA, HCC, CCA, PCA, and CRC cell lines, and xenograft mouse models	Inhibited cell proliferation, migration, invasion, cell cycle progression, tumor growth, and enhanced cell death	None in GI cancers	[192-197]
TT-232	PKM2	HCC, PAC, and CRC cell lines, and xenograft mouse models	Inhibited cell proliferation, tumor growth, and enhanced cell death	None in GI cancers	[198-200]
Targeting lactate biosynthesis
Dichloroacetate (DCA)	PDK	GC, ESCA, HCC, PAC, and CRC cell lines, xenograft models, and B6C3F1 mice	Reduced lactate production, cell proliferation, migration, and increased chemosensitivity. Showed synergistic anti-cancer effects in HCC. However, promoted hepatocarcinogenesis in B6C3F1 mice	CRC patient, phase I (NCT00566410)	[203-207]
Compound 24c	LDHA	PAC cell lines, and xenograft model	Suppressed cell proliferation, colony formation, enhanced cell apoptosis, arrested cell at G2 phase, repressed xenograft growth, and re-programmed cancer metabolism, with minimal impact on mouse weight	None in GI cancers	[210]
1-(Phenylseleno)-4-(Trifluoromethyl) Benzene (PSTMB)	LDHA	HCC and CRC cell lines	Inhibited cell proliferation, reduced cell viability, attenuated LDHA activity, lowered lactate levels, and induced mitochondria-mediated apoptosis	None in GI cancers	[211]
Oxamate	LDHA	GC, ESCA, HCC, PCA, and CRC cell lines	Suppressed LDHA activity, lactate production, cell proliferation, migration, MMP9 expression, pro-inflammatory cytokines, EMT transition, and AKT/ERK/mTOR signaling pathways, while enhanced apoptosis, senescence, protective autophagy, and metabolic rewiring	None in GI cancers	[212-218]
Galloflavin	LDHA	HCC, PCA, and CRC cell lines	Reduced ATPase activity and expression levels of heat shock proteins, inhibited cell proliferation, lactate production, pro-inflammatory cytokines, and EMT transition, while promoting apoptosis and senescence	None in GI cancers	[215,218-220]
FX11	LDHA	HCC, PCA, and CRC cell lines, and xenograft mouse models	FX11 reduced lactate production and ATP levels, suppressed cell proliferation, migration, invasion, and xenograft tumor growth, while enhancing apoptosis. However, in a PCA patient-derived mouse xenograft model, FX11 was only effective in attenuating tumor growth in the presence of mutant TP53	None in GI cancers	[221-225]
Gossypol (AT-101) or its derivatives	LDHA	GC, ESCA, HCC, PAC and CRC cell lines, GC and xenograft mouse models, and ESCA patient	Reduced cell viability, suppressed cell proliferation, migration, and tumor growth, down-regulated cancer stem cell markers CD133, Nanog, LC3, and YAP-1, enhanced apoptosis, protective autophagy. and complete response rate/prognosis	ESCA patient, phase I/II (NCT00561197)	[226-240]
Targeting lactate transportation
AZD3965	MCT1/2	GC, ESCA, HCC, CRC cell lines	Inhibited cell proliferation and tumor growth, while increasing intracellular lactate concentration, TCA-related metabolites, mitochondrial metabolism, and chemosensitivity. Also decreased intracellular pH	None in GI cancers	[242-246]
AR-C155858	MCT1/2	GC, PAC, and CRC cell lines, and xenograft mouse models	Inhibited cell proliferation, spheroid forming ability, and tumor growth, while decreased glycolysis and increased intracellular lactate concentration, TCA-related metabolites, mitochondrial metabolism, and chemosensitivity	None in GI cancers	[247-249]
Targeting mitochondrial OXPHOS
Metformin	Mitochondrial complex I	GC, ESCA, HCC, CCA, PAC, and CRC cell lines, xenograft models, and ESCA, HCC, CCA, PCA and CRC patients	Suppressed cell proliferation, migration, cell cycle progression, and tumor growth while increasing chemosensitivity and cell death. Also re-programmed the tumor immune microenvironment in ESCA patients	ESCA patient, phase II (ChiCTR-ICR-15005940), HCC patient, phase I (CTRI/2018/07/014865), CCA patient, phase Ib (NCT0249674), PCA patient, phase II (NCT01210911 and NCT01167738), and CRC patient, phase II (NCT01312467, NCT03047837, and NCT01941953)	[252-265]
Tamoxifen	Mitochondrial complex I	GC, ESCA, HCC, CCA, PAC and CRC cell lines, CRC murine model, and ESCA, HCC and PAC patients	Inhibited cell proliferation, tumor growth, metastasis, and increased chemosensitivity. However, no prolonged survival benefits have been observed in HCC patients, and in some cases, there may even be a higher risk of death	ESCA patient, phase I (NCT02513849), PAC patient, phase II[272-274], and HCC patient, phase III (NCT00003424)	[267-273,277]
IM156	Mitochondrial complex I	GC and CRC patients	Considered tolerable in human subjects, with stable disease being the most common response. Combinatorial therapy may be necessary for improved efficacy	GC and CRC patients, phase I (NCT03272256), and PAC patient, phase Ib (NCT05497778)	[278]
IACS-010759	Mitochondrial complex I	PAC cell lines, and CCA, PAC, and CRC patients	Reduced cell viability and generally well tolerated, but may induce neurotoxicity, peripheral neuropathy, and behavioral/physiological changes in mice. Increased blood lactate levels	CCA, PAC, and CRC patient, phase I (NCT03291938)	[279,280]
Atovaquone	Mitochondrial complex III	GC, HCC, PAC and CRC cell lines, and xenograft models	Reduced OXPHOS, oxygen consumption rate, cell viability, cell proliferation, and cell cycle progression. Inhibited tumor growth and enhanced cell death	None in GI cancers	[283-285]
Targeting TCA cycle
CPI-613	PDH and KGDHC	GC, ESCA, PAC and CRC cell lines, xenograft mouse models, and GC mouse model	Inhibited cell proliferation, cell viability, tumor growth, and metastasis, while increased cell death and chemosensitivity. In PAC patients, also increased the overall response rate	PAC patient, phase I (NCT01835041) and III (NCT03504423), HCC and CCA patients, phase I/II (NCT01766219), and CRC patients, phase I (NCT05070104 and NCT02232152)	[287-291]

GI: Gastrointestinal; ESCA: Esophageal cancer; GC: Gastric cancer; HCC: Hepatocellular carcinoma; CCA: Cholangiocarcinoma; PAC: Pancreatic cancer; CRC: Colorectal cancer; LDHA: Lactate dehydrogenase subunit A; MCT1/2: Monocarboxylate transporter family 1/2; HIF1A: Hypoxia inducible factor 1A; GLUT1: Glucose transporter 1; HK2: Hexokinase 2; PFKFB3: Fructose-2,6-biphosphatase 3; PKM2: Pyruvate kinase isozyme M2; PDK: Pyruvate dehydrogenase kinase; PDH: Pyruvate dehydrogenase; KGDHC: Alpha-ketoglutarate dehydrogenase complex; EMT: Epithelial-mesenchymal transition; OXPHOS: Oxidative phosphorylation.