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Yi-Yang Wen, Wei-Tao Liu, Hao-Ran Sun, Xin Ge, Zhu-Mei Shi, Min Wang, Wei Li, Jian-Ying Zhang, Ling-Zhi Liu, Bing-Hua Jiang
Dysregulation of miRNAs is important in breast cancer initiation and malignant progression. Recently we showed that miR-152 downregulation is associated with breast cancer development, yet the underlying mechanism of miR-152 remains to be well elucidated. In this study, we identified β-catenin as a new direct target of miR-152. MiR-152 inhibited cell proliferation by targeting and inhibiting both β-catenin and PKM2 expression. We found that miR-152 expression sensitized the breast cancer cells to paclitaxel treatment by inhibiting β-catenin and PKM2 expression...
November 21, 2017: Scientific Reports
Lin You, Hong Zhu, Chun Wang, Fang Wang, Yongjun Li, Yan Li, Yonglin Wang, Bin He
Scutellarin, one of natural flavonoids, is widely and clinically used for treating many diseases in China. Recently, scutellarin has demonstrated a broad spectrum of anti-proliferative activities against multiple cancer cell lines. However, the molecular mechanism of action remains to be investigated. We herein report the design and synthesis of biotinylated scutellareins as probes, which can be applied to discover scutellarein interacting proteins. Finally, we show that scutellarin directly targets pyruvate kinase M2 (PKM2) and inhibits its cytosolic activity to decrease glycolytic metabolism; on the other hand, scutellarin may also participate in regulating cell cycle and apoptotic proteins by activating MEK/ERK/PIN1 signaling pathway to promote the nuclear translocation of PKM2...
November 10, 2017: Bioorganic & Medicinal Chemistry Letters
Quan Yuan, Honghao Yu, Jianhua Chen, Xiaoyu Song, Li Sun
Osteosarcoma (OS) is the mostly diagnosed primary bone malignancy. Emerging evidence indicates that the activity of pyruvate kinase M2 (PKM2) isoform is crucial for the survival of tumor cells. In the present study, the effect of PKM2 knockdown on the proliferation and migration of OS cells were assessed both in vitro and in vivo. Small hairpin RNA (shRNA) technology were employed to suppresse the expression of PKM2 in MG-63 and Saos-2 cell lines. In vitro, shRNA-mediated knockdown of PKM2 efficiently inhibited cell proliferation, and induced G1 cell cycle arrest and apoptosis in both cell lines, which was associated with decreased expressions of cyclin D1 and Bcl-2 as well as increased expressions of Bax, cleaved-caspase-3, and cleaved-PARP...
November 16, 2017: Experimental Cell Research
Susan Hosseini Nasab, Neda Jooya, Aryan Esmaeili, Neda Zarrin Khameh, Concepcion Diaz-Arrastia, Mazdak Momeni
OBJECTIVES: To explore whether the metabolic switches proceed or succeed the histological changes in precancerous lesions. To validate pyruvate kinase isoform 1 (PKM1) and pyruvate kinase isoform 2 (PKM2) as a histological biomarker to predict the progression of endometrial hyperplasia into invasive cancer status. METHODS: The records of 56 patients with a primary diagnosis of complex hyperplasia with atypia after endometrial biopsy were selected and analyzed retrospectively...
January 1, 2017: Reproductive Sciences
Yiming Yang, Ke Wu, Yulin Liu, Liang Shi, Kaixiong Tao, Guobin Wang
BACKGROUNDS: Numerous studies have reported that aberrant pyruvate kinase M2 isoform (PKM2) expressed in cancer, indicating that PKM2 plays a critical role in tumor initiation and progression. Nevertheless, its prognostic value in breast cancer tumor is yet contentious. Therefore, we performed this meta-analysis to evaluate the prognostic significance of PKM2 in breast cancer. METHODS: Eligible relevant literatures were retrieved by searching PubMed, the Cochrane Library, Embase through December 2016...
November 2017: Medicine (Baltimore)
Shengtang Qin, Danli Yang, Kang Chen, Haolan Li, Liqiang Zhang, Yuan Li, Rongrong Le, Xiaojie Li, Shaorong Gao, Lan Kang
Aerobic glycolysis is one of the most important common characteristics in both cancer cells and stem cells. Metabolism switch has been discovered as an important early event in the process of reprogramming somatic cells to induced pluripotent stem cells (iPSCs). As a rate limiting kinase in glycolysis, Pkm2 has been reported playing critical roles in many tumors, yet its role in stem cells and iPSCs induction is poorly defined. In the present study, we showed that Pkm2 is a predominant pyruvate kinase in embryonic stem cells (ESCs), and its expression increases many pluripotent genes...
October 13, 2017: Oncotarget
Yan Liu, Hao Wu, Ying Mei, Xiong Ding, Xiaoli Yang, Changping Li, Mingming Deng, Jianping Gong
Pyruvate kinase M2 (PKM2), a key protein in glucose and lipid metabolism, has been reported to be related to carcinogenesis in various malignancies. However, its roles in hepatocellular carcinoma with cirrhotic liver (CL) and hepatocellular carcinoma with non-cirrhoticliver (NCL) haves not been investigated. In our study western bloting, qRT-PCR and immunohistochemistry were performed to evaluate the clinical significance of PKM2 protein expression in CL and NCL. The results revealed that PKM2 protein expression was significantly higher in HCC tissues than in their adjacent non-tumour tissues...
November 10, 2017: Scientific Reports
Robert G Shulman, Douglas L Rothman
Despite many decades of study there is a lack of a quantitative explanation for the Warburg effect in cancer. We propose that the glycogen shunt, a pathway recently shown to be critical for cancer cell survival, may explain the excess lactate generation under aerobic conditions characteristic of the Warburg effect. The proposal is based on research on yeast and mammalian muscle and brain that demonstrates that the glycogen shunt functions to maintain homeostasis of glycolytic intermediates and ATP during large shifts in glucose supply or demand...
November 2017: Trends in Cancer
Xinhua Xie, Xiaojia Huang, Hailin Tang, Feng Ye, Lu Yang, Xiaofang Guo, Zhi Tian, Cheng Peng, Xiaoming Xie
It has been reported that diallyl disulfide (DADS) has anti-proliferative activity in many cancers. The purpose of this study was to investigate the functions of DADS and the underlying mechanisms of its effect in breast cancer stem cells (BCSCs). Mammosphere formation assay, glucose consumption assay, lactate production assay and mouse xenograft experiments were performed to explore the functions of DADS in BCSCs. ATPase activity assay, western blotting and immunohistochemistry (IHC) assay were conduct to explore the mechanisms underlying the effects of DADS in BCSCs...
October 24, 2017: Current Cancer Drug Targets
Jun Huang, Ke Liu, Shan Zhu, Min Xie, Rui Kang, Lizhi Cao, Daolin Tang
Sepsis and septic shock remain challenging for intensive care units worldwide and have limited treatment options; therefore, identification of targetable key players in systemic inflammation and multiple organ failure is urgently needed. Here, we show that AMP-activated protein kinase (AMPK) is a negative regulator of bioenergetic reprogramming in immune cells and suppresses sepsis development in vivo. Mechanistically, AMPK deficiency increases pyruvate kinase isozyme M2 (PKM2)-dependent aerobic glycolysis, which leads to the release of high mobility group box 1 (HMGB1, a late mediator of lethal systemic inflammation) in macrophages and monocytes...
November 3, 2017: Brain, Behavior, and Immunity
H Zahid, K Subbaramaiah, N M Iyengar, X K Zhou, I-C Chen, P Bhardwaj, A Gucalp, M Morrow, C A Hudis, A J Dannenberg, K A Brown
BACKGROUND/OBJECTIVES: Obesity (body mass index (BMI) ⩾30) is associated with an increased risk of estrogen-dependent breast cancer after menopause. Levels of aromatase, the rate-limiting enzyme in estrogen biosynthesis, are elevated in breast tissue of obese women. Recently, the regulation of aromatase by the p53-HIF1α/PKM2 axis was characterized in adipose stromal cells (ASCs) of women with Li-Fraumeni Syndrome, a hereditary cancer syndrome that predisposes to estrogen-dependent breast cancer...
November 6, 2017: International Journal of Obesity: Journal of the International Association for the Study of Obesity
Zhixin Ling, Dachuang Liu, Guangyuan Zhang, Qing Liang, Ping Xiang, Yan Xu, Conghui Han, Tao Tao
Prostate cancer (PCa) is a leading cause of death among men. The dysregulation of metabolism and autophagy contributes to the progression of PCa. The transcription factor specificity protein 1 (Sp1) is implicated in the regulation of metabolism and autophagy. We confirmed that Sp1 is overexpressed in castration-resistant prostate cancer (CRPC) cells. However, the roles of Sp1 in PCa metabolism and autophagy remain unclear. Thus, in the present study, we retrieved the GSE35988 dataset from Gene Expression Omnibus (GEO) database to reinvestigate Sp1 expression and its role in PCa...
September 2017: Oncology Reports
Eva M Palsson-McDermott, Lydia Dyck, Zbigniew Zasłona, Deepthi Menon, Anne F McGettrick, Kingston H G Mills, Luke A O'Neill
Blocking interaction of the immune checkpoint receptor PD-1 with its ligand PD-L1 is associated with good clinical outcomes in a broad variety of malignancies. High levels of PD-L1 promote tumor growth by restraining CD8(+) T-cell responses against tumors. Limiting PD-L1 expression and function is therefore critical for allowing the development of antitumor immune responses and effective tumor clearance. Pyruvate kinase isoform M2 (PKM2) is also a key player in regulating cancer as well as immune responses...
2017: Frontiers in Immunology
Alexandre Vallée, Yves Lecarpentier, Rémy Guillevin, Jean-Noël Vallée
Entropy rate is increased by several metabolic and thermodynamics abnormalities in neurodegenerative diseases (NDs). Changes in Gibbs energy, heat production, ionic conductance or intracellular acidity are irreversibles processes which driven modifications of the entropy rate. The present review focusses on the thermodynamic implications in the reprogramming of cellular energy metabolism enabling in Alzheimer's disease (AD) through the opposite interplay of the molecular signaling pathways WNT/β-catenin and PPARγ...
October 24, 2017: Life Sciences
Smriti Singh, Sathiya Pandi Narayanan, Kajal Biswas, Amit Gupta, Neha Ahuja, Sandhya Yadav, Rajendra Kumar Panday, Atul Samaiya, Shyam K Sharan, Sanjeev Shukla
Aberrant alternative splicing and epigenetic changes are both associated with various cancers, but epigenetic regulation of alternative splicing in cancer is largely unknown. Here we report that the intragenic DNA methylation-mediated binding of Brother of Regulator of Imprinted Sites (BORIS) at the alternative exon of Pyruvate Kinase (PKM) is associated with cancer-specific splicing that promotes the Warburg effect and breast cancer progression. Interestingly, the inhibition of DNA methylation, BORIS depletion, or CRISPR/Cas9-mediated deletion of the BORIS binding site leads to a splicing switch from cancer-specific PKM2 to normal PKM1 isoform...
October 24, 2017: Proceedings of the National Academy of Sciences of the United States of America
Fabao Liu, Fengfei Ma, Yuyuan Wang, Ling Hao, Hao Zeng, Chenxi Jia, Yidan Wang, Peng Liu, Irene M Ong, Baobin Li, Guojun Chen, Jiaoyang Jiang, Shaoqin Gong, Lingjun Li, Wei Xu
Metabolic reprogramming is a hallmark of cancer. Herein we discover that the key glycolytic enzyme pyruvate kinase M2 isoform (PKM2), but not the related isoform PKM1, is methylated by co-activator-associated arginine methyltransferase 1 (CARM1). PKM2 methylation reversibly shifts the balance of metabolism from oxidative phosphorylation to aerobic glycolysis in breast cancer cells. Oxidative phosphorylation depends on mitochondrial calcium concentration, which becomes critical for cancer cell survival when PKM2 methylation is blocked...
November 2017: Nature Cell Biology
Karthigayan Shanmugasundaram, Bijaya K Nayak, William E Friedrichs, Dharam Kaushik, Ronald Rodriguez, Karen Block
The molecular mechanisms that couple glycolysis to cancer drug resistance remain unclear. Here we identify an ATP-binding motif within the NADPH oxidase isoform, NOX4, and show that ATP directly binds and negatively regulates NOX4 activity. We find that NOX4 localizes to the inner mitochondria membrane and that subcellular redistribution of ATP levels from the mitochondria act as an allosteric switch to activate NOX4. We provide evidence that NOX4-derived reactive oxygen species (ROS) inhibits P300/CBP-associated factor (PCAF)-dependent acetylation and lysosomal degradation of the pyruvate kinase-M2 isoform (PKM2)...
October 19, 2017: Nature Communications
Xuan Dung Ho, Phuong Phung, Van Q Le, Van H Nguyen, Ene Reimann, Ele Prans, Gea Kõks, Katre Maasalu, Nghi Tn Le, Le H Trinh, Hoang G Nguyen, Aare Märtson, Sulev Kõks
We performed whole transcriptome analysis of osteosarcoma bone samples. Initially, we sequenced total RNA from 36 fresh-frozen samples (18 tumoral bone samples and 18 non-tumoral paired samples) matching in pairs for each osteosarcoma patient. We also performed independent gene expression analysis of formalin-fixed paraffin-embedded samples to verify the RNAseq results. Formalin-fixed paraffin-embedded samples allowed us to analyze the effect of chemotherapy. Data were analyzed with DESeq2, edgeR and Reactome packages of R...
January 1, 2017: Experimental Biology and Medicine
Kishu Kitayama, Masakazu Yashiro, Tamami Morisaki, Yuichiro Miki, Tomohisa Okuno, Haruhito Kinoshita, Tatsunari Fukuoka, Hiroaki Kasashima, Go Masuda, Tsuyoshi Hasegawa, Katsunobu Sakurai, Naoshi Kubo, Kosei HIrakawa, Masaichi Ohira
The aim of this study was to analyze the significance of glucose metabolism-related enzymes in the proliferation of gastric cancer under hypoxia. Four hypoxia-resistant gastric cancer cell lines and 4 parent cell lines were used. RT-PCR was used to evaluate the mRNA expression levels of the following metabolism-related enzymes: pyruvate kinase isozymes M2 (PKM2), glutaminase (GLS), enolase 1 (ENO1), glucose-6-phosphate dehydrogenase (G6PDH), and PKM1. The effects of these enzymes on the proliferation of gastric cancer cells were examined using siRNAs, Shikonin as a PKM2 inhibitor, or BPTES as a GLS inhibitor, in vitro and in vivo...
October 15, 2017: Cancer Science
Sevki Adem, Veysel Comakli, Naim Uzun
It is well known that cancer cells have an altered metabolism both to meet the energy needs and to provide initial molecules for the synthesis of macromolecules. To cope with the new metabolic state, different forms of certain enzymes are expressed in extreme amounts. These enzymes are seen as very attractive targets to deal with cancer. Pyruvate kinases isoenzyme M2 (PKM2) is a key enzyme that determines whether glucose is used for energy or synthesis of biosynthetic molecules. The dimeric form of PKM2 main form in several cancer cells serves the formation of synthetic precursors required for the cell growth and proliferation from glycolytic intermediates...
October 10, 2017: Expert Opinion on Therapeutic Patents
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