Expression of pyruvate dehydrogenase kinase-1 in gastric cancer as a potential therapeutic target

Pyruvate dehydrogenase kinase 1 (PDK1) blockade triggers are well characterized in vitro metabolic alterations in cancer cells, including reduced glycolysis and increased glucose oxidation. Here, by gene expression profiling and digital pathology-mediated quantification of in situ markers in tumors, we investigated effects of PDK1 silencing on growth, angiogenesis and metabolic features of tumor xenografts formed by highly glycolytic OC316 and OVCAR3 ovarian cancer cells. Notably, at variance with the moderate antiproliferative effects observed in vitro, we found a dramatic negative impact of PDK1 silencing on tumor growth. These findings were associated with reduced angiogenesis and increased necrosis in the OC316 and OVCAR3 tumor models, respectively. Analysis of viable tumor areas uncovered increased proliferation as well as increased apoptosis in PDK1-silenced OVCAR3 tumors. Moreover, RNA profiling disclosed increased glucose catabolic pathways—comprising both oxidative phosphorylation and glycolysis—in PDK1-silenced OVCAR3 tumors, in line with the high mitotic activity detected in the viable rim of these tumors. Altogether, our findings add new evidence in support of a link between tumor metabolism and angiogenesis and remark on the importance of investigating net effects of modulations of metabolic pathways in the context of the tumor microenvironment.

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SAA1 is upregulated in gastric cancer-associated fibroblasts possibly by its enhancer activation

Carcinogenesis ◽

10.1093/carcin/bgaa131 ◽

2020 ◽

Author(s):

Yoshimi Yasukawa ◽

Naoko Hattori ◽

Naoko Iida ◽

Hideyuki Takeshima ◽

Masahiro Maeda ◽

...

Keyword(s):

Gastric Cancer ◽

Cancer Cells ◽

Chromatin Immunoprecipitation ◽

Therapeutic Target ◽

Cancer Associated Fibroblasts ◽

Promoting Effect ◽

Gastric Cancer Cells ◽

Potential Therapeutic Target ◽

Active Enhancer ◽

Serum Amyloid A1

Abstract Cancer-associated fibroblasts (CAFs) tend to have tumor-promoting capacity, and can provide therapeutic targets. Even without cancer cells, CAF phenotypes are stably maintained, and DNA methylation and H3K27me3 changes have been shown to be involved. Here, we searched for a potential therapeutic target in primary CAFs from gastric cancer and a mechanism for its dysregulation. Expression microarray using eight CAFs and seven non-CAFs (NCAFs) revealed that serum amyloid A1 (SAA1), which encodes an acute phase secreted protein, was second most upregulated in CAFs, following IGF2. Conditioned medium (CM) derived from SAA1-overexpressing NCAFs was shown to increase migration of gastric cancer cells compared to that from control NCAFs, and its tumor-promoting effect was comparable to that of CM from CAFs. In addition, increased migration of cancer cells by CM from CAFs was mostly canceled with CM from CAFs with SAA1 knockdown. Chromatin immunoprecipitation (ChIP)-quantitative PCR showed that CAFs had higher levels of H3K27ac, an active enhancer mark, in the promoter and the two far upstream regions of SAA1 than NCAFs. Also, BET bromodomain inhibitors, JQ1 and mivebresib, decreased SAA1 expression and tumor-promoting effects in CAFs, suggesting SAA1 upregulation by enhancer activation in CAFs. Our present data showed that SAA1 is a candidate therapeutic target from gastric CAFs and indicated that increased enhancer acetylation is important for its overexpression.

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Identification of ARGLU1 as a potential therapeutic target for gastric cancer based on genome-wide functional screening data

EBioMedicine ◽

10.1016/j.ebiom.2021.103436 ◽

2021 ◽

Vol 69 ◽

pp. 103436

Author(s):

Fangyuan Li ◽

Jianfang Li ◽

Junxian Yu ◽

Tao Pan ◽

Beiqin Yu ◽

...

Keyword(s):

Gastric Cancer ◽

Therapeutic Target ◽

Functional Screening ◽

Potential Therapeutic Target ◽

Genome Wide

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MiR-138 protects cardiac cells against hypoxia through modulation of glucose metabolism by targetting pyruvate dehydrogenase kinase 1

Bioscience Reports ◽

10.1042/bsr20170296 ◽

2017 ◽

Vol 37 (6) ◽

Cited By ~ 5

Author(s):

Hang Zhu ◽

Hao Xue ◽

Qin-Hua Jin ◽

Jun Guo ◽

Yun-Dai Chen

Keyword(s):

Pyruvate Dehydrogenase ◽

Mitochondrial Respiration ◽

Cardiac Cells ◽

Pyruvate Dehydrogenase Kinase ◽

Cellular Respiration ◽

Small Noncoding Rnas ◽

Direct Binding ◽

Inhibition Of Glycolysis ◽

Pyruvate Dehydrogenase Kinase 1 ◽

Novel Therapeutic Strategies

Dysfunction of cardiac cells under hypoxia has been identified as an essential event leading to myocytes functional failure. MiRNAs are importantly regulatory small-noncoding RNAs that negatively regulate gene expression through the direct binding of 3′-UTR region of their target mRNAs. Recent studies have demonstrated that miRNAs are aberrantly expressed in the cardiovascular system under pathological conditions.Pyruvate dehydrogenase kinase 1 (PDK1) is a kinase which phosphorylates pyruvate dehydrogenase to inactivate it, leading to elevated anaerobic glycolysis and decreased cellular respiration. In the present study, we report that miR-138 expressions were significantly suppressed under long exposure to hypoxia. In addition, overexpression of miR-138 protects human cardiac cells against hypoxia. We observed miR-138 inhibits glycolysis but promotes mitochondrial respiration through directly targetting PDK1. Moreover, we demonstrate that hypoxia induces cardiac cell death through increased glycolysis and decreased mitochondrial respiration. Inhibition of glycolysis by either glycolysis inhibitor or knockdown glycolysis enzymes, Glucose transportor 1 (Glut1) or PDK1 contributes to cardiac cells’ survival. The cell sentivity to hypoxia was recovered when the PDK1 level was restored in miR-138 overexpressing cardiac cells. The present study leads to the intervention of novel therapeutic strategies against cardiac cells dysfunction during surgery or ischemia.

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Identification of Novel Pyruvate Dehydrogenase Kinase 1 (PDK1) Inhibitors by Kinase Activity-Based High-Throughput Screening for Anticancer Therapeutics

ACS Combinatorial Science ◽

10.1021/acscombsci.8b00104 ◽

2018 ◽

Vol 20 (11) ◽

pp. 660-671 ◽

Cited By ~ 2

Author(s):

Wen Zhang ◽

Xiaohui Hu ◽

Harapriya Chakravarty ◽

Zheng Yang ◽

Kin Yip Tam

Keyword(s):

High Throughput ◽

Pyruvate Dehydrogenase ◽

High Throughput Screening ◽

Kinase Activity ◽

Pyruvate Dehydrogenase Kinase ◽

Anticancer Therapeutics ◽

Pyruvate Dehydrogenase Kinase 1

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A Novel Therapeutic Target, BACH1, Regulates Cancer Metabolism

10.20944/preprints202101.0626.v1 ◽

2021 ◽

Author(s):

Jiyoung Lee ◽

Joselyn Padilla

Keyword(s):

Cancer Cells ◽

Cancer Patients ◽

Transcriptional Activation ◽

Pyruvate Dehydrogenase ◽

Therapeutic Target ◽

Metabolic Pathways ◽

Cancer Metabolism ◽

Aerobic Glycolysis ◽

Pyruvate Dehydrogenase Kinase ◽

Migration And Invasion

BTB domain and CNC homology 1 (BACH1) is a highly expressed transcription factor in tumors including breast and lung, relative to their non-tumor tissues. BACH1 is known to regulate multiple physiological processes including heme homeostasis, oxidative stress response, senescence, cell cycle, and mitosis. In a tumor, BACH1 promotes invasion and metastasis of cancer cells, and the expression of BACH1 presents a poor outcome for cancer patients including breast cancer patients. Recent studies identified novel functional roles of BACH1 in the regulation of metabolic pathways in cancer cells. BACH1 inhibits mitochondrial metabolism through transcriptional suppression of mitochondrial membrane genes. In addition, BACH1 suppresses activity of pyruvate dehydrogenase (PDH), a key enzyme that converts pyruvate to acetyl-CoA for the citric acid (TCA) cycle through transcriptional activation of pyruvate dehydrogenase kinase (PDK). Moreover, BACH1 increases glucose uptake and lactate secretion in aerobic glycolysis through the expression of metabolic enzymes involved such as hexokinase 2 (HK2) and glyceraldehyde 3- phosphate dehydrogenase (GAPDH). Pharmacological or genetic inhibition of BACH1 could reprogramme metabolic pathways, subsequently rendering metabolic vulnerability of cancer cells. Furthermore, inhibition of BACH1 decreased antioxidant-induced glycolysis rates as well as reduced migration and invasion of cancer cells, suggesting BACH1 as a potentially useful cancer therapeutic target.

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