Prognostic significance of AKR1B10 in patients with resected lung adenocarcinoma

Hung, Jan Jong; Yeh, Yi Chen; Hsu, Wen Hu

doi:10.1111/1759-7714.12863

Cited by 19 publications

(21 citation statements)

References 21 publications

(39 reference statements)

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“…Literature already proved that the expression of the signaling molecules carcinoembryonic antigen-related cell adhesion molecule 6 (CEACAM6) and cystatin SN (CST1) regulate the LC migration while CEACAM1 regulates LC adhesion [67]. The aldo-keto reductase family 1, member B10 (aldose reductase, AKR1B10) overexpression proved a valid prognostic factor for high recurrence risk in patients with resected LC [68]. AKRC1 and AKR1C3 are regulated by nuclear factor-Y and found to be linked to LC in heavy smokers [69].…”

Section: Discussionmentioning

confidence: 99%

(−)-Oleocanthal as a Dual c-MET-COX2 Inhibitor for the Control of Lung Cancer

et al. 2020

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Lung cancer (LC) represents the topmost mortality-causing cancer in the U.S. LC patients have overall poor survival rate with limited available treatment options. Dysregulation of the mesenchymal epithelial transition factor (c-MET) and cyclooxygenase 2 (COX2) initiates aggressive LC profile in a subset of patients. The Mediterranean extra-virgin olive oil (EVOO)-rich diet already documented to reduce multiple malignancies incidence. (-)-Oleocanthal (OC) is a naturally occurring phenolic secoiridoid exclusively occurring in EVOO and showed documented anti-breast and other cancer activities via targeting c-MET. This study shows the novel ability of OC to suppress LC progression and metastasis through dual targeting of c-MET and COX-2. Western blot analysis and COX enzymatic assay showed significant reduction in the total and activated c-MET levels and inhibition of COX1/2 activity in the lung adenocarcinoma cells A549 and NCI-H322M, in vitro. In addition, OC treatment caused a dose-dependent inhibition of the HGF-induced LC cells migration. Daily oral treatment with 10 mg/kg OC for 8 weeks significantly suppressed the LC A549-Luc progression and prevented metastasis to brain and other organs in a nude mouse tail vein injection model. Further, microarray data of OC-treated lung tumors showed a distinct gene signature that confirmed the dual targeting of c-MET and COX2. Thus, the EVOO-based OC is an effective lead with translational potential for use as a prospective nutraceutical to control LC progression and metastasis.

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Section: Discussionmentioning

confidence: 99%

(−)-Oleocanthal as a Dual c-MET-COX2 Inhibitor for the Control of Lung Cancer

et al. 2020

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“…The ARKs, including AKR1B10 and AKR1C3, are also overexpressed in a number of premalignant and established cancers including liver cancer (76)(77)(78), and play a role in prostanoid synthesis which drives hormone-dependent cancers including prostate, breast, and endometrial ones (79)(80)(81). Heightened AKR1B10 overexpression is also critical to cancers associated with protein prenylation of mutant KRAS; which is a formidable prognostic indicator to tumor invasion, metastasis and progression (82)(83)(84), chemoresistance (85), radiation resistance (86), recurrence, tumor size and overall poor clinical outcomes (87)(88)(89). Downregulation of ARK1B10 observed in both glycolysis-null clones would favor a vulnerability to tumor growth.…”

Section: Reduction In Aldehyde Dehydrogenase Transcripts (Aldhs)mentioning

confidence: 99%

Whole-transcriptome Analysis of Fully Viable Energy Efficient Glycolytic-null Cancer Cells Established by Double Genetic Knockout of Lactate Dehydrogenase A/B or Glucose-6-Phosphate Isomerase

Mazzio

Badisa

Mack

et al. 2020

Cancer Genomics Proteomics

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Background/Aim: Nearly all mammalian tumors of diverse tissues are believed to be dependent on fermentative glycolysis, marked by elevated production of lactic acid and expression of glycolytic enzymes, most notably lactic acid dehydrogenase (LDH). Therefore, there has been significant interest in developing chemotherapy drugs that selectively target various isoforms of the LDH enzyme. However, considerable questions remain as to the consequences of biological ablation of LDH or upstream targeting of the glycolytic pathway. Materials and Methods: In this study, we explore the biochemical and whole transcriptomic effects of CRISPR-Cas9 gene knockout (KO) of lactate dehydrogenases A and B [LDHA/B double KO (DKO)] and glucose-6-phosphate isomerase (GPI KO) in the human colon cancer cell line LS174T, using Affymetrix 2.1 ST arrays. Results: The metabolic biochemical profiles corroborate that relative to wild type (WT), LDHA/B DKO produced no lactic acid, (GPI KO) produced minimal lactic acid and both KOs displayed higher mitochondrial respiration, and minimal use of glucose with no loss of cell viability. These findings show a high biochemical energy efficiency as measured by ATP in glycolysis-null cells. Next, transcriptomic analysis conducted on 48,226 mRNA transcripts reflect 273 differentially expressed genes (DEGS) in the GPI KO clone set, 193 DEGS in the LDHA/B DKO clone set with 47 DEGs common to both KO clones. Glycolytic-null cells reflect up-regulation in gene transcripts typically associated with nutrient deprivation / fasting and possible use of fats for energy: thioredoxin interacting protein (TXNIP), mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase 2 (HMGCS2), PPARγ coactivator 1α (PGC-1α), and acetyl-CoA acyltransferase 2 (ACAA2). Other changes in non-ergometric transcripts in both KOs show losses in "stemness", WNT signaling pathway, chemo/radiation resistance, retinoic acid synthesis, drug detoxification, androgen/estrogen activation, and extracellular matrix reprogramming genes. Conclusion: These findings demonstrate that: 1) The "Warburg effect" is dispensable, 2) loss of the LDHAB gene is not only inconsequential to viability but fosters greater mitochondrial energy, and 3) drugs that target LDHA/B are likely to be ineffective without a plausible combination second drug target. Common features across diverse mammalian tumors include the rapid glycolytic activity, greater expression of lactate dehydrogenases (LDH) and subsequent overproduction of lactic acid, occurring regardless of the presence of oxygen (Warburg effect) (1,2). This unique trait of cancer has been studied for decades, where researchers have geared off original focus from its role in metabolism to its role in acidification of the tumor microenvironment (TME), a formidable driving force for tumor growth, metastasis, aggressiveness, chemo/radiation resistance and loss of immune surveillance (3-8). This loss of immune surveillance 469 This article is freely accessible online.

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“…It is commonly expressed in normal epithelial tissues of the digestive tract and presents at very low level in non-gastrointestinal tissues [ 6 , 7 ]. Aberrant expression of AKR1B10 has been detected in multiple solid tumors such as hepatocellular cancer [ 8 ], lung cancer [ 9 ], breast cancer [ 10 ] and pancreatic cancer [ 11 ], and strongly associated with prognosis [ 12 – 15 ], and downregulated in malignancies of the digestive tract, such as gastric cancer and CRC [ 15 , 16 ]. AKR1B10 normally exerts a gastro-protective effect by metabolizing α, β-unsaturated carbonyl compounds produced by gut microbiota into less toxic hydroxyl compounds [ 17 ], promoting the synthesis of fatty acids or lipids in the digestive tract mucosa for the constant renewal of crypt cells [ 18 ], and mediating retinoid acid homeostasis and cell differentiation [ 10 ].…”

Section: Introductionmentioning

confidence: 99%

Loss of AKR1B10 promotes colorectal cancer cells proliferation and migration via regulating FGF1-dependent pathway

Yao

Wang

Zhou

et al. 2020

Aging

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Colorectal cancer (CRC) is a common malignancy worldwide with poor prognosis and survival rates. The aldo-keto reductase family 1 member B10 (AKR1B10) plays an important role in metabolism, cell proliferation and mobility, and is downregulated in CRC. We hypothesized that AKR1B10 would promote CRC genesis via a noncanonical oncogenic pathway and is a novel therapeutic target. In this study, AKR1B10 expression levels in 135 pairs of CRC and para-tumor tissues were examined, and its oncogenic role was determined using in vitro and in vivo functional assays following genetic manipulation of CRC cells. AKR1B10 was downregulated in CRC tissues compared to the adjacent normal colorectal tissues, and associated with the clinicopathological status of the patients. AKR1B10 depletion promoted the proliferation and migration of CRC cells in vitro , while its ectopic expression had the opposite effect. AKR1B10 was also significantly correlated with FGF1 gene and protein levels. Knockdown of AKR1B10 promoted tumor growth in vivo , and increased the expression of FGF1. Finally, AKR1B10 inhibited FGF1, and suppressed the proliferation and migration ability of CRC cells in an FGF1-dependent manner. In conclusion, AKR1B10 acts as a tumor suppressor in CRC by inactivating FGF1, and is a novel target for combination therapy of CRC.

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Prognostic significance of AKR1B10 in patients with resected lung adenocarcinoma

Cited by 19 publications

References 21 publications

(−)-Oleocanthal as a Dual c-MET-COX2 Inhibitor for the Control of Lung Cancer

(−)-Oleocanthal as a Dual c-MET-COX2 Inhibitor for the Control of Lung Cancer

Whole-transcriptome Analysis of Fully Viable Energy Efficient Glycolytic-null Cancer Cells Established by Double Genetic Knockout of Lactate Dehydrogenase A/B or Glucose-6-Phosphate Isomerase

Loss of AKR1B10 promotes colorectal cancer cells proliferation and migration via regulating FGF1-dependent pathway

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