KLK2

Gene Summary

Gene:KLK2; kallikrein related peptidase 2
Aliases: hK2, hGK-1, KLK2A2
Location:19q13.33
Summary:This gene encodes a member of the grandular kallikrein protein family. Kallikreins are a subgroup of serine proteases that are clustered on chromosome 19. Members of this family are involved in a diverse array of biological functions. The protein encoded by this gene is a highly active trypsin-like serine protease that selectively cleaves at arginine residues. This protein is primarily expressed in prostatic tissue and is responsible for cleaving pro-prostate-specific antigen into its enzymatically active form. This gene is highly expressed in prostate tumor cells and may be a prognostic maker for prostate cancer risk. Alternate splicing results in both coding and non-coding transcript variants. [provided by RefSeq, Jan 2012]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:kallikrein-2
Source:NCBIAccessed: 30 August, 2019

Ontology:

What does this gene/protein do?
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Pathways:What pathways are this gene/protein implicaed in?
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Cancer Overview

Research Indicators

Publications Per Year (1994-2019)
Graph generated 30 August 2019 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

  • Alleles
  • Unfolded Protein Response
  • Cancer DNA
  • Androgens
  • Prostatic Neoplasms, Castration-Resistant
  • Base Sequence
  • Cancer Gene Expression Regulation
  • Biomarkers, Tumor
  • Transcription Factors
  • Gene Expression Profiling
  • Prostate-Specific Antigen
  • Chromosome 19
  • Tosyl Compounds
  • Cell Proliferation
  • Molecular Sequence Data
  • Tissue Kallikreins
  • Promoter Regions
  • Genotype
  • Messenger RNA
  • Serine Endopeptidases
  • Oncogene Fusion Proteins
  • Kallikreins
  • Genome-Wide Association Study
  • Prostate
  • Prostate Cancer
  • RTPCR
  • Uterine Cancer
  • Androgen Receptors
  • Tissue Distribution
  • Genetic Predisposition
  • Survival Rate
  • Multivariate Analysis
  • Cell Surface Receptors
  • Risk Factors
  • Ovarian Cancer
  • Transfection
  • Neoplasm Recurrence, Local
  • Case-Control Studies
  • Transcription
  • Transcriptome
  • Single Nucleotide Polymorphism
  • MicroRNAs
Tag cloud generated 30 August, 2019 using data from PubMed, MeSH and CancerIndex

Specific Cancers (3)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: KLK2 (cancer-related)

Li Y, Xu Q, Yang W, et al.
Oleanolic acid reduces aerobic glycolysis-associated proliferation by inhibiting yes-associated protein in gastric cancer cells.
Gene. 2019; 712:143956 [PubMed] Related Publications
Gastric cancer represents a common malignancy of digestive tract with high incidence and mortality. Increasing evidence suggests that the growth of gastric tumor cells relies largely on aerobic glycolysis. Currently, many potential anti-cancer candidates are derived from natural products. Here, we evaluated the effects of oleanolic acid (OA), a triterpenoid component widely found in the plants of Oleaceae family, on aerobic glycolysis and proliferation in human MKN-45 and SGC-7901 gastric cancer cells. Our results demonstrated that OA reduced the viability and proliferation of gastric cancer cells and inhibited the expression of cyclin A and cyclin-dependent kinase 2. OA blocked glycolysis in these cells evidenced by decreases in the uptake and consumption of glucose, intracellular lactate levels and extracellular acidification rate. Glycolysis inhibitor 2-deoxy-d-glucose, similar to OA, suppressed gastric cancer cell proliferation. OA also decreased the expression and intracellular activities of glycolysis rate-limiting enzymes hexokinase 2 (HK2) and phosphofructokinase 1 (PFK1). Moreover, OA downregulated the expression of hypoxia inducible factor-1α (HIF-1α) and decreased its nuclear abundance. Upregulation of HIF-1α by deferoxamine rescued OA-inhibited HK2 and PFK1. Furthermore, OA reduced the nuclear abundance of yes-associated protein (YAP) in gastric tumor cells. YAP inhibitor verteporfin, similar to OA, downregulated the expression of HIF-1α and glycolytic enzymes in gastric cancer cells; whereas overexpression of YAP abrogated all these effects of OA. Collectively, inhibition of YAP was responsible for OA blockade of HIF-1α-mediated aerobic glycolysis and proliferation in human gastric tumor cells. OA could be developed as a promising candidate for gastric cancer treatment.

Yoo JJ, Yu SJ, Na J, et al.
Hexokinase-II Inhibition Synergistically Augments the Anti-tumor Efficacy of Sorafenib in Hepatocellular Carcinoma.
Int J Mol Sci. 2019; 20(6) [PubMed] Free Access to Full Article Related Publications
This study aimed to examine whether inhibition of hexokinase (HK)-II activity enhances the efficacy of sorafenib in in-vivo models of hepatocellular carcinoma (HCC), and to evaluate the prognostic implication of HK-II expression in patients with HCC. We used 3-bromopyruvate (3-BP), a HK-II inhibitor to target HK-II. The human HCC cell line was tested as both subcutaneous and orthotopic tumor xenograft models in BALB/c nu/nu mice. The prognostic role of HK-II was evaluated in data from HCC patients in The Cancer Genome Atlas (TCGA) database and validated in patients treated with sorafenib. Quantitative real-time PCR, western blot analysis, and immunohistochemical staining revealed that HK-II expression is upregulated in the presence of sorafenib. Further analysis of the endoplasmic reticulum-stress network model in two different murine HCC models showed that the introduction of additional stress by 3-BP treatment synergistically increased the in vivo/vitro efficacy of sorafenib. We found that HCC patients with increased HK-II expression in the TCGA database showed poor overall survival, and also confirmed similar results for TCGA database HCC patients who had undergone sorafenib treatment. These results suggest that HK-II is a promising therapeutic target to enhance the efficacy of sorafenib and that HK-II expression might be a prognostic factor in HCC.

Chen J, Yu Y, Li H, et al.
Long non-coding RNA PVT1 promotes tumor progression by regulating the miR-143/HK2 axis in gallbladder cancer.
Mol Cancer. 2019; 18(1):33 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: The long non-coding RNA PVT1 (lncRNA PVT1) has been reported to act as an oncogenic regulator of several cancers. However, its expression and function in gallbladder cancer (GBC) remain largely unknown.
METHODS: In situ hybridization (ISH) and quantitative real-time PCR (qPCR) were performed to detect the expression of PVT1 and miR-143 in GBC tissues and cell lines. Immunohistochemistry (IHC) assays were performed to assess the expression of the hexokinase 2 (HK2) protein. The relationships among PVT1, miR-143 and HK2 were evaluated using dual-luciferase reporter, RNA immunoprecipitation (RIP) and biotin pull-down assays. The biological functions of PVT1, miR-143 and HK2 in GBC cells were explored with cell counting kit 8 (CCK-8), 5-ethynyl-20-deoxyuridine (EdU), colony formation, transwell, wound healing and glucose metabolism assays in vitro. For in vivo experiments, a xenograft model was used to investigate the effects of PVT1 and HK2 on GBC.
RESULTS: PVT1 was upregulated in GBC tissues and cells and was positively associated with malignancies and worse overall survival. PVT1 knockdown inhibited cell proliferation, migration, and invasion in vitro and restrained tumor growth in vivo. Further studies demonstrated that PVT1 positively regulated HK2 expression via its competing endogenous RNA (ceRNA) activity on miR-143. Additionally, HK2 expression and function were positively correlated with PVT1. Furthermore, we observed that the PVT1/miR-143/HK2 axis promoted cell proliferation and metastasis by regulating aerobic glucose metabolism in GBC cells.
CONCLUSIONS: The results of our study reveal a potential ceRNA regulatory pathway in which PVT1 modulates HK2 expression by competitively binding to endogenous miR-143 in GBC cells, which may provide new insights into novel molecular therapeutic targets for GBC.

Hong X, Yu JJ
Silencing of lysyl oxidase‑like 2 inhibits the migration, invasion and epithelial‑to‑mesenchymal transition of renal cell carcinoma cells through the Src/FAK signaling pathway.
Int J Oncol. 2019; 54(5):1676-1690 [PubMed] Free Access to Full Article Related Publications
The aim of the present study was to investigate the effects of lysyl oxidase‑like 2 (LOXL2) on the invasion, migration and epithelial‑to‑mesenchymal transition (EMT) of renal cell carcinoma (RCC) cells through the steroid receptor coactivator (Src)/focal adhesion kinase (FAK) signaling pathway. RCC tissues and adjacent normal tissues were collected from 80 patients with RCC. Immunohistochemistry was used to determine the positive expression rate of the LOXL2 protein. The expression levels of LOXL2 in the HK‑2, 786‑O, ACHN, Caki1 and A498 cell lines were detected by reverse transcription‑quantitative polymerase chain reaction (RT‑qPCR). The high LOXL2‑expressing 786‑O cells were selected for gene silencing experiments, whereas Caki1 cells, which exhibited low LOXL2 expression, were used for overexpression experiments. RT‑qPCR and western blot analysis were applied to determine the expression of LOXL2, FAK, Src, matrix metalloproteinase (MMP)‑9, epithelial (E)‑cadherin, neuronal (N)‑cadherin and vimentin. A MTT assay, a Transwell assay, a wound healing assay and flow cytometry were performed to detect cell proliferation, invasion, migration, cell cycle distribution and apoptosis, respectively. The protein expression rate of LOXL2 in RCC tissues was higher compared with that in adjacent normal tissues. Compared with adjacent normal tissues, the mRNA and protein expression levels of LOXL2, FAK, Src, MMP‑9, N‑cadherin and vimentin and the levels of FAK and Src phosphorylation were increased, while the mRNA and protein expression levels of E‑cadherin were decreased in RCC tissues. Following the transfection of 786‑O cells with small interfering (si) RNA against LOXL2, the mRNA and protein expression levels of FAK, Src, MMP‑9, N‑cadherin and vimentin and the levels of phosphorylated FAK and Src were notably decreased in the si‑LOXL2 and PP2 inhibitor treated groups, while that of E‑cadherin was substantially increased. Additionally, cell proliferation, invasion, migration and the percentage of RCC cells in the G1 phase were reduced, and cell apoptosis was increased. Additionally, Caki1 cells transfected with LOXL2 exhibited an opposite trend. In summary, these results indicate that LOXL2 silencing inhibits the invasion, migration and EMT in RCC cells through inhibition of the Src/FAK signaling pathway.

Wang L, Liu Y, Zhao TL, et al.
Topotecan induces apoptosis via ASCT2 mediated oxidative stress in gastric cancer.
Phytomedicine. 2019; 57:117-128 [PubMed] Related Publications
BACKGROUND: Topotecan (TPT) is a Topo I inhibitor and shows obvious anti-cancer effects on gastric cancer. Cancer cells reprogram their metabolic pathways to increase nutrients uptake, which has already been a hallmark of cancer. But the effect of TPT on metabolism in gastric cancer remains unknown.
PURPOSE: To investigate the effect of TPT on metabolism in gastric cancer.
METHODS: ATP production was measured by ATP Assay kit. Glucose and glutamine uptake were measured by Glucose (HK) Assay Kit and Glutamine/Glutamate Determination Kit respectively. To detect glutathione (GSH) concentration and reactive oxygen species (ROS) generation, GSH and GSSG Assay Kit and ROS Assay Kit were adopted. Apoptosis rates, mitochondrial membrane potential (MMP) were determined by flow cytometry and protein levels were analyzed by immumohistochemical staining and western blotting.
RESULTS: TPT increased ATP production. TPT promoted glucose uptake possibly via up-regulation of hexokinase 2 (HK2) or glucose transporter 1 (GLUT1) expression, while decreased glutamine uptake by down-regulation of ASCT2 expression. ASCT2 inhibitor GPNA and ASCT2 knockdown significantly suppressed the growth of gastric cancer cells. Inhibition of ASCT2 reduced glutamine uptake which led to decreased production of GSH and increased ROS level. ASCT2 knockdown induced apoptosis via the mitochondrial pathway and weakened anti-cancer effect of TPT.
CONCLUSION: TPT inhibits glutamine uptake via down-regulation of ASCT2 which causes oxidative stress and induces apoptosis through the mitochondrial pathway. Moreover, TPT inhibits proliferation partially via ASCT2. These observations reveal a previously undescribed mechanism of ASCT2 regulated gastric cancer proliferation and demonstrate ASCT2 is a potential anti-cancer target of TPT.

Kim DJ, Vo MT, Choi SH, et al.
Tristetraprolin-mediated hexokinase 2 expression regulation contributes to glycolysis in cancer cells.
Mol Biol Cell. 2019; 30(5):542-553 [PubMed] Free Access to Full Article Related Publications
Hexokinase 2 (HK2) catalyzes the first step of glycolysis and is up-regulated in cancer cells. The mechanism has not been fully elucidated. Tristetraprolin (TTP) is an AU-rich element (ARE)-binding protein that inhibits the expression of ARE-containing genes by enhancing mRNA degradation. TTP expression is down-regulated in cancer cells. We demonstrated that TTP is critical for down-regulation of HK2 expression in cancer cells. HK2 mRNA contains an ARE within its 3'-UTR. TTP binds to HK2 3'-UTR and enhances degradation of HK2 mRNA. TTP overexpression decreased HK2 expression and suppressed the glycolytic capacity of cancer cells, measured as glucose uptake and production of glucose-6-phosphate, pyruvate, and lactate. TTP overexpression reduced both the extracellular acidification rate (ECAR) and the oxygen consumption rate (OCR) of cancer cells. Ectopic expression of HK2 in cancer cells attenuated the reduction in glycolytic capacity, ECAR, and OCR from TTP. Taken together, these findings suggest that TTP acts as a negative regulator of HK2 expression and glucose metabolism in cancer cells.

Dunn J, Ferluga S, Sharma V, et al.
Proteomic analysis discovers the differential expression of novel proteins and phosphoproteins in meningioma including NEK9, HK2 and SET and deregulation of RNA metabolism.
EBioMedicine. 2019; 40:77-91 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Meningioma is the most frequent primary intracranial tumour. Surgical resection remains the main therapeutic option as pharmacological intervention is hampered by poor knowledge of their proteomic signature. There is an urgent need to identify new therapeutic targets and biomarkers of meningioma.
METHODS: We performed proteomic profiling of grade I, II and III frozen meningioma specimens and three normal healthy human meninges using LC-MS/MS to analyse global proteins, enriched phosphoproteins and phosphopeptides. Differential expression and functional annotation of proteins was completed using Perseus, IPA® and DAVID. We validated differential expression of proteins and phosphoproteins by Western blot on a meningioma validation set and by immunohistochemistry.
FINDINGS: We quantified 3888 proteins and 3074 phosphoproteins across all meningioma grades and normal meninges. Bioinformatics analysis revealed commonly upregulated proteins and phosphoproteins to be enriched in Gene Ontology terms associated with RNA metabolism. Validation studies confirmed significant overexpression of proteins such as EGFR and CKAP4 across all grades, as well as the aberrant activation of the downstream PI3K/AKT pathway, which seems differential between grades. Further, we validated upregulation of the total and activated phosphorylated form of the NIMA-related kinase, NEK9, involved in mitotic progression. Novel proteins identified and validated in meningioma included the nuclear proto-oncogene SET, the splicing factor SF2/ASF and the higher-grade specific protein, HK2, involved in cellular metabolism.
INTERPRETATION: Overall, we generated a proteomic thesaurus of meningiomas for the identification of potential biomarkers and therapeutic targets. FUND: This study was supported by Brain Tumour Research.

Gan BL, Zhang LJ, Gao L, et al.
Downregulation of miR‑224‑5p in prostate cancer and its relevant molecular mechanism via TCGA, GEO database and in silico analyses.
Oncol Rep. 2018; 40(6):3171-3188 [PubMed] Free Access to Full Article Related Publications
The function of the expression of microRNA (miR)‑224‑5p in prostate adenocarcinoma (PCa) remains to be elucidated, therefore, the present study aimed to investigate the clinical significance and potential molecular mechanism of miR‑224‑5p in PCa. Data on the expression of miR‑224‑5p in PCa were extracted from The Cancer Genome Atlas (TCGA), Gene Expression Omnibus (GEO), ArrayExpress and previous literature, and meta‑analyses with standardized mean difference (SMD) and summary receiver operating characteristic (sROC) methods were performed for statistical analyses. The prospective target genes of miR‑224‑5p were collected by overlapping the differentially expressed mRNAs in TCGA and GEO, and target genes predicted by miRWalk2.0. Subsequently, in silico analysis was performed to examine the associated pathways of miR‑224‑5p in PCa. The expression of miR‑224‑5p was markedly lower in PCa; the overall SMD was ‑0.562, and overall sROC area under the curve was 0.80. In addition, Kyoto Encyclopedia of Genes and Genomes analysis revealed that the prospective target genes of miR‑224‑5p were largely enriched in the amino sugar and nucleotide sugar metabolism signaling pathway, and three genes [UDP‑N‑acetylglucosamine pyrophosphorylase 1 (UAP1), hexokinase 2 (HK2) and chitinase 1 (CHIT1)] enriched in this pathway showed higher expression (P<0.05). In addition, key genes in the protein‑protein interaction network analysis [DNA topoisomerase 2‑α (TOP2A), ATP citrate lyase (ACLY) and ribonucleotide reductase regulatory subunit M2 (RRM2)] exhibited significantly increased expression (P<0.05). The results suggested that the downregulated expression of miR‑224‑5p may be associated with the clinical progression and prognosis of PCa. Furthermore, miR‑224‑5p likely exerts its effects by targeting genes, including UAP1, HK2, CHIT1, TOP2A, ACLY and RRM2. However, in vivo and in vitro experiments are required to confirm these findings.

Tang Y, Fan M, Choi YJ, et al.
Sika deer (Cervus nippon) velvet antler extract attenuates prostate cancer in xenograft model.
Biosci Biotechnol Biochem. 2019; 83(2):348-356 [PubMed] Related Publications
The present study determines whether antler extract (AE) possesses inhibitory effects in a prostate cancer (PC) xenograft model and explores the underlying mechanism. After therapeutic intervention for two weeks, AE significantly inhibited prostate cancer xenograft tumor growth by 65.08%, and prostate-specific antigen (PSA) and serum dihydrotestosterone (DHT) levels. However, AE increased the serum testosterone level compared to the vehicle control group. Furthermore, our investigation of the inhibitory effects on angiogenesis and epithelial-to-mesenchymal transition (EMT)-related genes revealed that AE downregulated matrix metalloproteinase 2 (MMP)-2, (MMP)-9, vascular endothelial growth factor (VEGF), zinc finger protein (SNAIL1), twist-related protein 1 (TWIST1), and zinc-finger E-box-binding homeobox 1 (ZEB1) in vivo. In contrast, AE increased tissue inhibitor of MMP (TIMP)-1, (TIMP)-2, and E-cadherin. The results suggest that AE possesses potent anti-PC activity, and this is the first report on the anti-PC effect of AE in vivo.

Mao Z, Ji A, Yang K, et al.
Diagnostic performance of PCA3 and hK2 in combination with serum PSA for prostate cancer.
Medicine (Baltimore). 2018; 97(42):e12806 [PubMed] Free Access to Full Article Related Publications
OBJECTIVES: The prostate cancer gene 3 (PCA3), human kallikrein 2, and miRNA-141 are promising prostate cancer (Pca) specific biomarkers. Our aim was to evaluate the detection of PCA3, human glandular kallikrein 2 (hk2), and miRNA-141 mRNA in peripheral blood of patients received prostate biopsy. What's more, we want to detect the value of combination of PSA (prostate specific antigen) in the early diagnosis of PCa.
MATERIALS AND METHODS: Hundred patients were divided into 2 groups according to the results of pathologic diagnosis. Quantitative real-time PCR (qRT-PCR) was used to evaluate the mRNA of PCA3, hk2, and miRNA-141 in peripheral blood. At the same time, analyze those clinical outcomes used in the patients. We compared these different outcomes to evaluate the value of new molecular markers.
RESULTS: The level of mRNA of PCA3, hK2, and miR-141 in Pca group were significantly higher than that in BPH. PSA had the highest sensitivity in predicting Pca diagnosis (76.7%); PCA3 had the highest specificity (82.5%). And the combination of PCA3, PSA, and hK2 improved area under the curve (AUC)-receiver operating characteristic (ROC) curve largely, especially those with PSA 4-10ng/mL.
CONCLUSIONS: PCA3, hK2, and miRNA-141 were biomarkers of Pca with potential clinical application value, especially in patients with PSA gray area. Combining PCA3, PSA, and hK2 performed better than individual biomarkers alone in predicting Pca.

Zhao L, Quan J, Li Z, et al.
MicroRNA‑222‑3p promotes tumor cell migration and invasion and inhibits apoptosis, and is correlated with an unfavorable prognosis of patients with renal cell carcinoma.
Int J Mol Med. 2019; 43(1):525-534 [PubMed] Related Publications
The aim of the present study was to investigate the role of microRNA (miR)‑222‑3p in renal cell carcinoma (RCC). The expression level of miR‑222‑3p was detected in RCC tissues and cell lines (ACHN, 786‑O, Caki‑1 and 769‑P) and was identified to be significantly upregulated compared with the level in adjacent normal renal tissues and HK‑2 cells. Further in vitro experiments demonstrated that the over-expression of miR‑222‑3p promoted the migration and invasion, and attenuated the apoptosis of 786‑O cells, whereas the knockdown of miR‑222‑3p suppressed the migration and invasion and induced the apoptosis of 786‑O cells. Similar results were observed in the ACHN cell line in terms of migration, invasion and apoptosis. Furthermore, the expression level of miR‑222‑3p was measured in 42 RCC formaldehyde‑fixed paraffin‑embedded samples, and the association between the expression of miR‑222‑3p and the pathological characteristics and overall survival rate of patients with RCC was analyzed. The results demonstrated that patients with a higher expression of miR‑222‑3p had a significantly lower overall survival rate, compared with those with a lower expression of miR‑222‑3p [hazard ratio (HR)=5.120; P=0.036]. Multivariate analysis identified that patients with a higher expression of miR‑222‑3p retained the statistically significant decrease in overall survival rate compared with patients with a lower expression of miR‑222‑3p (HR=5.636; P=0.030). Furthermore, Kaplan‑Meier survival curves indicated that patients with higher miR‑222‑3p had significantly lower overall survival rates compared with patients with lower miR‑222‑3p (P=0.020). Taken together, these results suggested that miR‑222‑3p serves as an onco‑miR in RCC and may be a potential prognostic biomarker and therapeutic target in patients with RCC.

Yang J, Chen Y, Lu J, et al.
Identification and characterization of novel fusion genes in prostate cancer by targeted RNA capture and next-generation sequencing.
Acta Biochim Biophys Sin (Shanghai). 2018; 50(11):1166-1172 [PubMed] Related Publications
Gene fusions play critical roles in the development and progression of prostate cancer, and have been used as molecular biomarkers for diagnosis of the malignant disease. To further explore the novel fusions in prostate cancer, we performed targeted RNA capture and next-generation sequencing in a cohort of 52 prostate cancer patients, identified and validated 14 fusion events (7 types of fusion genes) in 12 cases, including three novel fusion genes. We characterized a chromosome rearrangement-induced trigenic KLK2-DGKB-ETV1 fusion, which may function as a non-coding RNA to upregulate the expression of the wild-type ETV1 protein in the tumor tissue. Additionally, we detected two novel fusion forms of HNRNPA2B1-ETV1 and SLC45A2-AMACR fusions, respectively. Interestingly, fusion events participated by kinase genes, which frequently occurred in other human cancers, were not present in these prostate cancer cases, suggesting discrepant gene fusion patterns in different cancers. These findings expand the genetic spectrum of prostate cancer and provide insight into diagnosis of this prevalent disease.

Wang P, Magdolen V, Seidl C, et al.
Kallikrein-related peptidases 4, 5, 6 and 7 regulate tumour-associated factors in serous ovarian cancer.
Br J Cancer. 2018; 119(7):1-9 [PubMed] Article available free on PMC after 02/10/2019 Related Publications
BACKGROUND: Tissue kallikrein-related peptidases 4, 5, 6 and 7 (KLK4-7) strongly increase the malignancy of ovarian cancer cells. Deciphering their downstream effectors, we aimed at finding new potential prognostic biomarkers and treatment targets for ovarian cancer patients. KLK4-7-transfected (OV-KLK4-7) and vector-control OV-MZ-6 (OV-VC) ovarian cancer cells were established to select differentially regulated factors.
METHODS: With three independent approaches, PCR arrays, genome-wide microarray and proteome analyses, we identified 10 candidates (MSN, KRT19, COL5A2, COL1A2, BMP5, F10, KRT7, JUNB, BMP4, MMP1). To determine differential protein expression, we performed western blot analyses, immunofluorescence and immunohistochemistry for four candidates (MSN, KRT19, KRT7, JUNB) in cells, tumour xenograft and patient-derived tissues.
RESULTS: We demonstrated that KLK4-7 clearly regulates expression of MSN, KRT19, KRT7 and JUNB at the mRNA and protein levels in ovarian cancer cells and tissues. Protein expression of the top-upregulated effectors, MSN and KRT19, was investigated by immunohistochemistry in patients afflicted with serous ovarian cancer and related to KLK4-7 immunoexpression. Significant positive associations were found for KRT19/KLK4, KRT19/KLK5 and MSN/KLK7.
CONCLUSION: These findings imply that KLK4-7 exert key modulatory effects on other cancer-related genes and proteins in ovarian cancer. These downstream effectors of KLK4-7, MSN and KRT19 may represent important therapeutic targets in serous ovarian cancer.

Cheng Y, Lu Y, Zhang D, et al.
Metastatic cancer cells compensate for low energy supplies in hostile microenvironments with bioenergetic adaptation and metabolic reprogramming.
Int J Oncol. 2018; 53(6):2590-2604 [PubMed] Related Publications
Metastasis accounts for the majority of cancer-related mortalities, and the complex processes of metastasis remain the least understood aspect of cancer biology. Metabolic reprogramming is associated with cancer cell survival and metastasis in a hostile envi-ronment with a limited nutrient supply, such as solid tumors. Little is known regarding the differences of bioenergetic adaptation between primary tumor cells and metastatic tumor cells in unfavorable microenvironments; to clarify these differences, the present study aimed to compare metabolic reprogramming of primary tumor cells and metastatic tumor cells. SW620 metastatic tumor cells exhibited stronger bioenergetic adaptation in unfavorable conditions compared with SW480 primary tumor-derived cells, as determined by the sustained elevation of glycolysis and regulation of the cell cycle. This remarkable glycolytic ability of SW620 cells was associated with high expression levels of hexokinase (HK)1, HK2, glucose transporter type 1 and hypoxia-inducible factor 1α. Compared with SW480 cells, the expression of cell cycle regulatory proteins was effectively inhibited in SW620 cells to sustain cell survival when there was a lack of energy. Furthermore, SW620 cells exhibited a stronger mesenchymal phenotype and stem cell characteristics compared with SW480 cells; CD133 and CD166 were highly expressed in SW620 cells, whereas expression was not detected in SW480 cells. These data may explain why metastatic cancer cells exhibit greater microenvironmental adaptability and survivability; specifically, this may be achieved by upregulating glycolysis, optimizing the cell cycle and reprogramming cell metabolism. The present study may provide a target metabolic pathway for cancer metastasis therapy.

Jin ML, Kim YW, Jeong KW
BAF53A regulates androgen receptor-mediated gene expression and proliferation in LNCaP cells.
Biochem Biophys Res Commun. 2018; 505(2):618-623 [PubMed] Related Publications
The actin-like protein of the SWI/SNF complex, BAF53A, regulates gene expression by the gene-specific chromatin remodeling of target genes. However, the function of BAF53A in the androgen receptor pathway in prostate cancer cells remains unclear. Here, we demonstrated that BAF53A positively regulates the expression of endogenous AR target genes (e.g. PSA, TMPRSS2, FKBP5, and KLK2) in LNCaP cells. It functions as a coactivator in AR-mediated transcription by interacting with other nuclear receptor coactivators, such as p300 and FLII, and is associated with AR in the presence of dihydrotestosterone (DHT). The DHT-induced recruitment of BAF53A to the proximal and distal androgen response elements (AREs) of the PSA gene in the presence of BRG1 (but not BRM) was inhibited by an AR antagonist, suggesting the coactivator function of BAF53A in the SWI/SNF complex. Depletion of BAF53A in LNCaP cells resulted in a significant decrease in growth rate. Furthermore, the expression of BAF53A in prostate cancer tissue was significantly elevated, compared to that in normal prostate tissue, and correlated with the expression of AR, and BRG1, but not BRM. Therefore, our results suggested that BAF53A plays an important role in the expression of AR target genes in prostate cancer, and can be used clinically for the treatment of prostate cancer.

Cheng C, Xie Z, Li Y, et al.
PTBP1 knockdown overcomes the resistance to vincristine and oxaliplatin in drug-resistant colon cancer cells through regulation of glycolysis.
Biomed Pharmacother. 2018; 108:194-200 [PubMed] Related Publications
Drug-resistant cancer cells exhibit increased glycolysis, and targeting glycolysis is considered as a novel strategy to overcome drug resistance. Polypyrimidine tract-binding protein (PTBP1) has been found to be a regulator of glycolysis, however, the role of PTBP1 in drug resistance remains to be elucidated. Herein, we found that PTBP1 was highly expressed in two drug-resistant colon cancer cell lines, vincristine-resistant HCT-8 cell line (HCT-8/V) and oxaliplatin-resistant HCT116 cell line (HCT116/L-OHP). The levels of glucose consumption and lactate production as well as expression of pyruvate kinase M2 isoform (PKM2) and hexokinase II (HK2) were elevated, while PKM1 level was reduced in HCT-8/V and HCT116/L-OHP cells when compared with the HCT-8 and HCT116 cells. PTBP1 knockdown enhanced the sensitivity of HCT-8/V and HCT116/L-OHP cells to vincristine and oxaliplatin, and caused reduction in glucose consumption and lactate production. PKM2 expression, but not HK2, was decreased and PKM1 expression level was increased in cells transfected with si-PTBP1. In addition, PTBP1 overexpression significantly induced glycolysis and reduced drug sensitivity, whereas the effects were attenuated by si-PKM2. Treatment with 2-deoxyglucose (2-DG) also attenuated the effect of PTBP1 overexpression on drug sensitivity. In conclusion, PTBP1 knockdown enhanced the sensitivity of drug-resistant colon cancer cells to vincristine and oxaliplatin through repression of glycolysis. Our study provided a promising therapeutic strategy to overcome drug resistance in colon cancer cells.

Nwosu ZC, Battello N, Rothley M, et al.
Liver cancer cell lines distinctly mimic the metabolic gene expression pattern of the corresponding human tumours.
J Exp Clin Cancer Res. 2018; 37(1):211 [PubMed] Article available free on PMC after 02/10/2019 Related Publications
BACKGROUND: Although metabolism is profoundly altered in human liver cancer, the extent to which experimental models, e.g. cell lines, mimic those alterations is unresolved. Here, we aimed to determine the resemblance of hepatocellular carcinoma (HCC) cell lines to human liver tumours, specifically in the expression of deregulated metabolic targets in clinical tissue samples.
METHODS: We compared the overall gene expression profile of poorly-differentiated (HLE, HLF, SNU-449) to well-differentiated (HUH7, HEPG2, HEP3B) HCC cell lines in three publicly available microarray datasets. Three thousand and eighty-five differentially expressed genes in ≥2 datasets (P < 0.05) were used for pathway enrichment and gene ontology (GO) analyses. Further, we compared the topmost gene expression, pathways, and GO from poorly differentiated cell lines to the pattern from four human HCC datasets (623 tumour tissues). In well- versus poorly differentiated cell lines, and in representative models HLE and HUH7 cells, we specifically assessed the expression pattern of 634 consistently deregulated metabolic genes in human HCC. These data were complemented by quantitative PCR, proteomics, metabolomics and assessment of response to thirteen metabolism-targeting compounds in HLE versus HUH7 cells.
RESULTS: We found that poorly-differentiated HCC cells display upregulated MAPK/RAS/NFkB signaling, focal adhesion, and downregulated complement/coagulation cascade, PPAR-signaling, among pathway alterations seen in clinical tumour datasets. In HLE cells, 148 downregulated metabolic genes in liver tumours also showed low gene/protein expression - notably in fatty acid β-oxidation (e.g. ACAA1/2, ACADSB, HADH), urea cycle (e.g. CPS1, ARG1, ASL), molecule transport (e.g. SLC2A2, SLC7A1, SLC25A15/20), and amino acid metabolism (e.g. PHGDH, PSAT1, GOT1, GLUD1). In contrast, HUH7 cells showed a higher expression of 98 metabolic targets upregulated in tumours (e.g. HK2, PKM, PSPH, GLUL, ASNS, and fatty acid synthesis enzymes ACLY, FASN). Metabolomics revealed that the genomic portrait of HLE cells co-exist with profound reliance on glutamine to fuel tricarboxylic acid cycle, whereas HUH7 cells use both glucose and glutamine. Targeting glutamine pathway selectively suppressed the proliferation of HLE cells.
CONCLUSIONS: We report a yet unappreciated distinct expression pattern of clinically-relevant metabolic genes in HCC cell lines, which could enable the identification and therapeutic targeting of metabolic vulnerabilities at various liver cancer stages.

Hillebrand AC, Pizzolato LS, Neto BS, et al.
Androgen receptor isoforms expression in benign prostatic hyperplasia and primary prostate cancer.
PLoS One. 2018; 13(7):e0200613 [PubMed] Article available free on PMC after 02/10/2019 Related Publications
The role of molecular changes in the androgen receptor (AR) as AR variants (AR-Vs) is not clear in the pathophysiology of benign prostatic hyperplasia (BPH) and hormone-naïve PCa. The aim of the current work was to identify the presence of AR isoforms in benign tissue and primary PCa, and to evaluate the possible association with tumor aggressiveness and biochemical recurrence in primary PCa. The mRNA levels of full length AR (AR-FL) and AR-Vs (AR-V1, AR-V4 and AR-V7) were measured using RT-qPCR. The protein expression of AR-FL (AR-CTD and AR-NTD) and AR-V7 were evaluated by the H-Score in immunohistochemistry (IHC). All investigated mRNA targets were expressed both in BPH and PCa. AR-FL mRNA levels were similar in both groups. AR-V4 mRNA expression showed higher levels in BPH, and AR-V1 and AR-V7 mRNA expression were higher in PCa. The AR-V7 protein showed a similar H-Score in both groups, while AR-CTD and AR-NTD were higher in nuclei of epithelial cells from BPH. These results support the assumption that these constitutively active isoforms of AR are involved in the pathophysiology of primary PCa and BPH. The role of AR-Vs and their possible modulation by steroid tissue levels in distinct types of prostate tumors needs to be elucidated to help guide the best clinical management of these diseases.

Zhang S, Pei M, Li Z, et al.
Double-negative feedback interaction between DNA methyltransferase 3A and microRNA-145 in the Warburg effect of ovarian cancer cells.
Cancer Sci. 2018; 109(9):2734-2745 [PubMed] Article available free on PMC after 02/10/2019 Related Publications
Ovarian cancer is the most lethal gynecological malignancy because of its poor prognosis. The Warburg effect is one of the key mechanisms mediating cancer progression. Molecules targeting the Warburg effect are therefore of significant therapeutic value for the treatment of cancers. Many microRNAs (miR) are dysregulated in cancers, and aberrant miR expression patterns have been suggested to correlate with the Warburg effect in cancer cells. In our study, we found that miR-145 negatively correlated with DNA methyltransferase (DNMT)3A expression at cellular/histological levels. miR-145 inhibited the Warburg effect by targeting HK2. Luciferase reporter assays confirmed that miR-145-mediated downregulation of DNMT3A occurred through direct targeting of its mRNA 3'-UTRs, whereas methylation-specific PCR (MSP) assays found that knockdown of DNMT3A increased mRNA level of miR-145 and decreased methylation levels of promoter regions in the miR-145 precursor gene, thus suggesting a crucial crosstalk between miR-145 and DNMT3A by a double-negative feedback loop. DNMT3A promoted the Warburg effect through miR-145. Coimmunoprecipitation assays confirmed no direct binding between DNMT3A and HK2. In conclusion, a feedback loop between miR-145 and DNMT3A is a potent signature for the Warburg effect in ovarian cancer, promising a potential target for improved anticancer treatment.

Suh S, Kim YH, Goh TS, et al.
mRNA Expression of SLC5A5 and SLC2A Family Genes in Papillary Thyroid Cancer: An Analysis of The Cancer Genome Atlas.
Yonsei Med J. 2018; 59(6):746-753 [PubMed] Article available free on PMC after 02/10/2019 Related Publications
PURPOSE: The present study investigated the dynamics and prognostic role of messenger RNA (mRNA) expression responsible for ¹⁸F-fluorodeoxyglucose (FDG) uptake in FDG positron emission tomography (PET) and radioactive iodine (¹³¹I) uptake in whole-body radioactive iodine scans (WBS) in papillary thyroid cancer (PTC) patients.
MATERIALS AND METHODS: The primary and processed data were downloaded from the Genomic Data Commons Data Portal. Expression data for sodium/iodide symporter (solute carrier family 5 member 5, SLC5A5), hexokinase (HK1-3), glucose-6-phosphate dehydrogenase (G6PD), and glucose transporter (solute carrier family 2, SLC2A1-4) mRNA were collected.
RESULTS: Expression of SLC5A5 mRNA were negatively correlated with SLC2A1 mRNA and positively correlated with SLC2A4 mRNA. In PTC with BRAF mutations, expressions of SLC2A1, SLC2A3, HK2, and HK3 mRNA were higher than those in PTC without BRAF mutations. Expression of SLC5A5, SLC2A4, HK1, and G6PD mRNA was lower in PTC without BRAF mutation. PTCs with higher expression of SLC5A5 mRNA had more favorable disease-free survival, but no association with overall survival.
CONCLUSION: Expression of SLC5A5 mRNA was negatively correlated with SLC2A1 mRNA. This finding provides a molecular basis for the management of PTC with negative WBS using ¹⁸F-FDG PET scans. In addition, higher expression of SLC5A5 mRNA was associated with less PTC recurrence, but not with deaths.

Wang R, Ma X, Su S, Liu Y
Triptolide antagonized the cisplatin resistance in human ovarian cancer cell line A2780/CP70 via hsa-mir-6751.
Future Med Chem. 2018; 10(16):1947-1955 [PubMed] Related Publications
AIM: We aimed to investigate the effect of triptolide on cisplatin resistance in ovarian cancer cell lines.
METHODS: The apoptosis of ovarian cancer cell lines A2780 and A2780/CP70 was determined by flow cytometry. Protein expression levels of  Hexokinase 2 (HK2) were detected by western blot. Possible mRNAs which target HK 2 expression were predicted through online tools miRbase.
RESULTS: Triptolide-promoted cell apoptosis of cisplatin-resistant ovarian cancer cell line A2780/CP70. Triptolide treatment sensitized the effect of cisplatin in A2780/CP70, as evidenced by decreased survival fraction of A2780/CP70 cells. Mechanically, triptolide treatment inhibited HK 2 expression in A2780/CP70 cells. In addition, Hsa-mir-6751 expression level was upregulated in A2780/CP70 cells after triptolide treatment.

Han X, Yang Y, Sun Y, et al.
LncRNA TUG1 affects cell viability by regulating glycolysis in osteosarcoma cells.
Gene. 2018; 674:87-92 [PubMed] Related Publications
Osteosarcoma is an aggressive malignant neoplasm in teenagers and young adults. Long non-coding RNA (lncRNA) taurine-upregulated gene 1 (TUG1) is considered as an oncogene in osteosarcoma. However, the mechanism of TUG1 in regulating osteosarcoma has not been fully understood. We aimed to investigate whether the metabolic alteration is involved in the effect of TUG1 on osteosarcoma cells. Herein, we found that TUG1 was overexpressed in osteosarcoma cells compared with the normal osteoblastic cell line. Knockdown of TUG1 inhibited glucose consumption, lactate production and cell viability of osteosarcoma cells. Overexpression of TUG1 induced cell viability, whereas the induction was attenuated by 2-DG. The aberrant expression of TUG1 markedly affected the expression of hexokinase-2 (HK2). Knockdown of HK2 weakened the effect of TUG1 overexpression on glycolysis in osteosarcoma cells. We concluded that glycolysis was involved in the effect of TUG1 on cell viability of osteosarcoma cells. HK2 might be an important molecule by which TUG1 affected the glycolysis.

Tyszka-Czochara M, Bukowska-Strakova K, Kocemba-Pilarczyk KA, Majka M
Caffeic Acid Targets AMPK Signaling and Regulates Tricarboxylic Acid Cycle Anaplerosis while Metformin Downregulates HIF-1α-Induced Glycolytic Enzymes in Human Cervical Squamous Cell Carcinoma Lines.
Nutrients. 2018; 10(7) [PubMed] Article available free on PMC after 02/10/2019 Related Publications
The small molecules, natural antioxidant Caffeic Acid (trans-3,4-Dihydroxycinnamic acid CA) and anti-diabetic drug Metformin (Met), activate 5′-adenosine monophosphate-activated protein kinase (AMPK) and interfere with metabolic reprogramming in human cervical squamous carcinoma cells. Here, to gain more insight into the ability of CA, Met and the combination of both compounds to impair aerobic glycolysis (the “Warburg effect”) and disrupt bioenergetics of cancer cells, we employed the cervical tumor cell lines C-4I and HTB-35/SiHa. In epithelial C-4I cells derived from solid tumors, CA alleviated glutamine anaplerosis by downregulation of Glutaminase (GLS) and Malic Enzyme 1 (ME1), which resulted in the reduction of NADPH levels. CA treatment of the cells altered tricarboxylic acid (TCA) cycle supplementation with pyruvate via Pyruvate Dehydrogenase Complex (PDH), increased ROS formation and enhanced cell death. Additionally, CA and CA/Met evoked intracellular energetic stress, which was followed by activation of AMPK and the impairment of unsaturated FA de novo synthesis. In invasive HTB-35 cells, Met inhibited Hypoxia-inducible Factor 1 (HIF-1α) and suppressed the expression of the proteins involved in the “Warburg effect”, such as glucose transporters (

Chen J, Cao S, Situ B, et al.
Metabolic reprogramming-based characterization of circulating tumor cells in prostate cancer.
J Exp Clin Cancer Res. 2018; 37(1):127 [PubMed] Article available free on PMC after 02/10/2019 Related Publications
BACKGROUND: Circulating tumor cells (CTCs), an advantageous target of liquid biopsy, is an important biomarker for the prognosis and monitoring of cancer. Currently, detection techniques for CTCs are mainly based on the physical and/or epithelial characteristics of tumor cells. However, biofunctional activity markers that can indicate the high metastatic capacity of CTCs are lacking.
METHODS: Functional microarray, quantitative real-time polymerase chain reaction, and Western blot were used on five prostate cancer cell lines with different metastatic capacities to identify the metastasis-related metabolic genes. The identified genes were detected in the CTCs of 64 clinical samples using the RNA in situ hybridization. A multi-criteria weighted model was used to determine the optimal metabolic markers for the CTCs test. Based on five fluorescent signals targeting DAPI, CD45, metabolic, epithelial (EpCAM/CKs), and mesenchymal (Vimentin/Twist) markers, the filtration-enriched CTCs were classified as GM
RESULTS: Eight metastasis-related metabolic genes were identified, including HK2, PDP2, G6PD, PGK1, PHKA1, PYGL, PDK1, and PKM2. Among them, PGK1 and G6PD were determined as optimal glucose metabolic (GM) markers for CTCs. GM
CONCLUSIONS: The metabolic marker (PGK1/G6PD) is determined as the indicator for the biofunctional activity analysis of CTCs, compared with the existing morphological (EMT) classification on CTCs. The metabolic characterization of CTCs demonstrates that hypermetabolic GM

Filippou PS, Ren AH, Bala S, et al.
Biochemical characterization of human tissue kallikrein 15 and examination of its potential role in cancer.
Clin Biochem. 2018; 58:108-115 [PubMed] Related Publications
OBJECTIVE: Human tissue kallikrein 15 (KLK15) is the last cloned member of the KLK-related gene family. Despite being implicated in multiple cancers, its pathophysiological role remains unknown. We aimed to biochemically characterize KLK15 and preliminarily study its role in cancer.
DESIGN & METHODS: Recombinant KLK15 protein was produced, purified to homogeneity and quantified by mass spectrometry (parallel reaction monitoring analysis). We profiled the enzymatic activity of KLK15 using fluorogenic peptide substrates, and performed kinetic analysis to discover the cleavage sites. As KLK15 has mainly been associated with prostate cancer, we used a degradomic approach and subsequent KEGG pathway analysis to identify a number of putative protein substrates in the KLK15-treated prostate cancer cell line PC3.
RESULTS: We discovered trypsin-like activity in KLK15, finding that it cleaves preferentially after arginine (R). The enzymatic activity of KLK15 was regulated by different factors such as pH, cations and serine protease inhibitors. Notably, we revealed that KLK15 most likely interacts with the extracellular matrix (ECM) receptor group.
CONCLUSION: To our knowledge, this is the first study that experimentally verifies the trypsin-like activity of KLK15. We show here for the first time that KLK15 may be able to cleave many ECM components, similar to several members of the KLK family. Thus the protease could potentially be linked to tumorigenesis by promoting metastasis via this mechanism.

Wang M, Wang W, Wang J, Zhang J
MiR-182 promotes glucose metabolism by upregulating hypoxia-inducible factor 1α in NSCLC cells.
Biochem Biophys Res Commun. 2018; 504(2):400-405 [PubMed] Related Publications
OBJECTIVE: This study aims to demonstrate the role of miR-182 in the glucose metabolism of NSCLC cells and the potential mechanism.
METHODS: MTT Cytotoxicity Assay was used to measure the function of differentially expressed miR-182 on two NSCLC cell lines proliferation. Metabolite analysis was introduced to monitor the glucose consumption, lactate release and glycolytic intermediate metabolites. The mRNA level of critical genes involved in glycolysis was detected by qRT-PCR. The 3'UTRs of predicted gene with a miR-182 binding site and their seed-sequence-mutated version were cloned downstream to the ORF of a Renilla luciferase reporter gene and the ability of miR-182 to downregulate luciferase expression was assessed.
RESULTS: MiR-182 had significantly improved proliferation of NSCLC cell lines. Metabolite analysis of the cells with strengthened miR-182 revealed significantly increased glucose consumption and lactate release, as well as glycolytic intermediate metabolites, or conversely. Among a panel of genes controlling glucose metabolism, miR-182 exhibited significantly influence on ENO1, GLUT1, HIF-1α, HK1, HK2, LDHA and PDK1, especially HIF-1α. For the predicted target gene HIF1AN, the wild-type but not mutated 3'UTR, responded to miR-182  b y directing ∼45% reduction of reporter gene expression.
CONCLUSION: MiR-182 promotes glucose metabolism by upregulating HIF-1α in NSCLC cells.

Mota MSV, Jackson WP, Bailey SK, et al.
Deficiency of tumor suppressor Merlin facilitates metabolic adaptation by co-operative engagement of SMAD-Hippo signaling in breast cancer.
Carcinogenesis. 2018; 39(9):1165-1175 [PubMed] Article available free on PMC after 21/09/2019 Related Publications
The NF2 gene encodes the tumor and metastasis suppressor protein Merlin. Merlin exerts its tumor suppressive role by inhibiting proliferation and inducing contact-growth inhibition and apoptosis. In the current investigation, we determined that loss of Merlin in breast cancer tissues is concordant with the loss of the inhibitory SMAD, SMAD7, of the TGF-β pathway. This was reflected as dysregulated activation of TGF-β signaling that co-operatively engaged with effectors of the Hippo pathway (YAP/TAZ/TEAD). As a consequence, the loss of Merlin in breast cancer resulted in a significant metabolic and bioenergetic adaptation of cells characterized by increased aerobic glycolysis and decreased oxygen consumption. Mechanistically, we determined that the co-operative activity of the Hippo and TGF-β transcription effectors caused upregulation of the long non-coding RNA Urothelial Cancer-Associated 1 (UCA1) that disengaged Merlin's check on STAT3 activity. The consequent upregulation of Hexokinase 2 (HK2) enabled a metabolic shift towards aerobic glycolysis. In fact, Merlin deficiency engendered cellular dependence on this metabolic adaptation, endorsing a critical role for Merlin in regulating cellular metabolism. This is the first report of Merlin functioning as a molecular restraint on cellular metabolism. Thus, breast cancer patients whose tumors demonstrate concordant loss of Merlin and SMAD7 may benefit from an approach of incorporating STAT3 inhibitors.

Zhang K, Zhang M, Jiang H, et al.
Down-regulation of miR-214 inhibits proliferation and glycolysis in non-small-cell lung cancer cells via down-regulating the expression of hexokinase 2 and pyruvate kinase isozyme M2.
Biomed Pharmacother. 2018; 105:545-552 [PubMed] Related Publications
Glycolysis is a metabolic pathway that is enhanced in cancer cells. miR-214 plays an important role in cancer development and can modulate glycolysis. However, whether miR-214 can regulate glycolysis in non-small-cell lung cancer (NSCLC) cells has not yet been investigated. The expression levels of miR-214 in 7 NSCLC cell lines were measured by qRT-PCR. MTT assay was performed to evaluate the cell proliferation. Glucose consumption and lactate production were measured to assess the level of glycolysis. The expression of hexokinase 2 (HK2) and pyruvate kinase isozyme M2 (PKM2) was measured by qRT-PCR and western blot analysis. Luciferase reporter assay was carried out to confirm the target gene of miR-214. The levels of PTEN, p-Akt, Akt, p-mTOR, mTOR, p-S6K, and S6K were assessed by western blot analysis. Results showed that miR-214 levels were significantly increased in the 7 NSCLC cell lines compared with those in the human bronchial epithelial cell line. Down-regulation of miR-214 inhibited cell proliferation, glucose consumption, lactate production, and expression of HK2 and PKM2 in NSCLC cells. We also confirmed that miR-214 directly targeted PTEN and regulated the PTEN/Akt/mTOR pathway. Inhibition of the PTEN/Akt/mTOR pathway attenuated the effect of miR-214 mimics on glucose consumption, lactate production, and expression of HK2 and PKM2 in NSCLC cells. These results demonstrated that miR-214 down-regulation inhibited cell proliferation and glycolysis by down-regulating the expression of HK2 and PKM2 via the PTEN/Akt/mTOR pathway in NSCLC cells. Hence, our findings suggested that miR-214 might serve as a novel therapeutic target for NSCLC.

Hui L, Zhang J, Guo X
MiR-125b-5p suppressed the glycolysis of laryngeal squamous cell carcinoma by down-regulating hexokinase-2.
Biomed Pharmacother. 2018; 103:1194-1201 [PubMed] Related Publications
Laryngeal squamous cell carcinoma (LSCC) is the most common form of laryngeal carcinoma with poor prognosis. Exploring novel factors involved in the progression of LSCC is quite necessary for understanding the mechanisms and designing therapeutic strategies for LSCC. In this study, we showed that miR-125b-5p was significantly down-regulated in LSCC tissues and cell lines. The decreased expression of miR-125b-5p was associated with the tumor differentiation, metastasis and high clinical stage of the LSCC patients. Overexpression of miR-125b-5p suppressed the proliferation and induced apoptosis of LSCC cells. Bioinformatics analysis predicted hexokinase-2 (HK2), an essential enzyme involved in the glycolysis of cancer cells, as one of the downstream targets of miR-125b-5p. Further molecular studies showed that highly expressed miR-125b-5p bound the 3'-UTR of HK2 and decreased both the mRNA and protein levels of HK2. Consistent with the function of HK2 in glycolytic metabolism, overexpression of miR-125b-5p significantly suppressed the glucose consumption and lactate production of LSCC cells. Notably, restoration the expression of HK2 attenuated the inhibitory effect of miR-125b-5p on the glycolysis of LSCC cells. The inverse correlation between the expression of miR-125b-5p and HK2 in LSCC tissues further supported the involvement of miR-125b-5p-HK2 axis in the progression of LSCC. Collectively, these finding suggested the miR-125b-5p-HK2 pathway as a novel mechanism in regulating the glycolysis and progression of LSCC.

Kleszcz R, Paluszczak J, Krajka-Kuźniak V, Baer-Dubowska W
The inhibition of c-MYC transcription factor modulates the expression of glycolytic and glutaminolytic enzymes in FaDu hypopharyngeal carcinoma cells.
Adv Clin Exp Med. 2018; 27(6):735-742 [PubMed] Related Publications
BACKGROUND: Cancer cells are dependent on aerobic glycolysis for energy production and increased glutamine consumption. HIF-1α and c-MYC transcription factors regulate the expression of glycolytic and glutaminolytic genes. Their activity may be repressed by SIRT6. Head and neck carcinomas show frequent activation of c-MYC function and SIRT6 down-regulation, which contributes to a strong dependence on glucose and glutamine availability.
OBJECTIVES: The aim of this study was to compare the influence of HIF-1α and c-MYC inhibitors (KG-548 and 10058-F4, respectively) and potential SIRT6 inducers - resveratrol and its synthetic derivative DMU-212 with the effect of glycolysis and glutaminolysis inhibitors (2-deoxyglucose and aminooxyacetic acid, respectively) on the metabolism and expression of metabolic enzymes in FaDu hypopharyngeal carcinoma cells.
MATERIAL AND METHODS: Cell viability was assessed by means of an MTT assay. Quantitative PCR was performed to evaluate the expression of SIRT6, HIF-1α, c-MYC, GLUT1, SLC1A5, HK2, PFKM, PKM2, LDHA, GLS, and GDH. The release of glycolysis and glutaminolysis end-products into the culture medium - lactate and ammonia, respectively - was assessed using standard colorimetric assays.
RESULTS: Lactate production was significantly inhibited by 10058-F4, KG-548, and 2-deoxyglucose. Moreover, 10058-F4 strongly reduced the amount of ammonia release. The effects of 10058-F4 activity can be attributed to a reduction in the expression of PKM2 and LDHA. On the other hand, the induction of SIRT6 expression by resveratrol and DMU-212 was not associated with significant modulation of the expression of metabolic enzymes.
CONCLUSIONS: Overall, the results of this study indicate that the inhibition of c-MYC may be considered to be a promising strategy of the modulation of cancer-related metabolic changes in head and neck carcinomas.

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