Oridonin interrupts cellular bioenergetics to suppress glioma cell growth by down‐regulating PCK2

Lin, Jianhu; Wu, Shanshan; Ye, Sisi; Papa, Akuetteh Percy David; Yang, Jianjing; Huang, Shengwei; Arthur, Gifty; Zhuge, Qichuan; Zhang, Yu

doi:10.1002/ptr.7009

Title: Oridonin interrupts cellular bioenergetics to suppress glioma cell growth by down‐regulating PCK2

Journal Article · Wed Jan 13 00:00:00 EST 2021 · PTR. Phytotherapy research

DOI:https://doi.org/10.1002/ptr.7009· OSTI ID:1784569

^[1]; Wu, Shanshan ^[1]; Ye, Sisi ^[1]; Papa, Akuetteh Percy David ^[1]; Yang, Jianjing ^[1]; Huang, Shengwei ^[1]; Arthur, Gifty ^[2]; Zhuge, Qichuan ^[1]; Zhang, Yu ^[1]

Zhejiang Provincial Key Laboratory of Aging and Neurological Disorder Research, Department of Neurosurgery The First Affiliated Hospital of Wenzhou Medical University Wenzhou China
Anfoega Catholic Hospital Volta Region Ghana

We aim to evaluate the tumor metabolic suppressive activity of Oridonin (extract of Rabdosia rubescens ) in glioma and elucidate its potential mechanism. Effects of Oridonin on U251/U87 cells were determined by CCK8, RTCA, colony formation, flow cytometry, wound healing, and Transwell assay. Xenograft tumor model to evaluate the effect of Oridonin on glioma cells in vivo. Cellular bioenergetics were measured by Seahorse. RNA‐seq was performed to screen potential biological pathways in Oridonin treated cells. Bioinformatics analysis of PCK2 in glioma was performed based on TCGA/CGGA. Endogenous PCK2 was knocked‐down by lentivirus packaged shRNA. We found Oridonin significantly inhibited cell growth in U251/U87 in vitro and in vivo. Both oxygen consumption rate (OCR) and extracellular acidification rate (ECAR) were decreased in Oridonin‐treated U251/U87 cells. Oridonin treatment led to PCK2 down‐regulation. Additionally, PCK2 was up‐regulated in higher grade glioma and correlated with poor outcomes. Furthermore, PCK2 depletion significantly inhibited cell growth and decreased OCR/ECAR in U251/U87 which coincided with the effects of Oridonin. Therefore, we evaluated the potent anti‐tumor property of Oridonin in glioma. Importantly, we demonstrated that PCK2 might be a novel target of Oridonin on glioma by inducing energy crisis and increasing oxidative stress.

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Sponsoring Organization:: USDOE

OSTI ID:: 1784569

Journal Information:: PTR. Phytotherapy research, Journal Name: PTR. Phytotherapy research Vol. 35 Journal Issue: 5; ISSN 0951-418X

Publisher:: Wiley Blackwell (John Wiley & Sons)Copyright Statement

Country of Publication:: FAO

Language:: English

References (43)

Molecular mechanisms of oridonin-induced apoptosis and autophagy in murine fibrosarcoma L929 cells Cheng, Yan; Qiu, Feng; Ikejima, Takashi Autophagy, Vol. 5, Issue 3 https://doi.org/10.4161/auto.5.3.7896	journal	April 2009
Metabolic reprogramming by PCK1 promotes TCA cataplerosis, oxidative stress and apoptosis in liver cancer cells and suppresses hepatocellular carcinoma Liu, Meng-Xi; Jin, Lei; Sun, Si-Jia Oncogene, Vol. 37, Issue 12 https://doi.org/10.1038/s41388-017-0070-6	journal	January 2018
Involvement of Glutathione Depletion in Selective Cytotoxicity of Oridonin to p53-Mutant Esophageal Squamous Carcinoma Cells Li, Yinchao; Li, Nana; Shi, Jianxiang Frontiers in Oncology, Vol. 9 https://doi.org/10.3389/fonc.2019.01525	journal	January 2020
SIRT2 Promotes the Migration and Invasion of Gastric Cancer through RAS/ERK/JNK/MMP-9 Pathway by Increasing PEPCK1-Related Metabolism Li, Yang; Zhang, Mingming; Dorfman, Robert G. Neoplasia, Vol. 20, Issue 7 https://doi.org/10.1016/j.neo.2018.03.008	journal	July 2018
Gluconeogenesis in cancer cells – Repurposing of a starvation-induced metabolic pathway? Grasmann, Gabriele; Smolle, Elisabeth; Olschewski, Horst Biochimica et Biophysica Acta (BBA) - Reviews on Cancer, Vol. 1872, Issue 1 https://doi.org/10.1016/j.bbcan.2019.05.006	journal	August 2019
Oridonin is a covalent NLRP3 inhibitor with strong anti-inflammasome activity He, Hongbin; Jiang, Hua; Chen, Yun Nature Communications, Vol. 9, Issue 1 https://doi.org/10.1038/s41467-018-04947-6	journal	June 2018
The Effects of Severe Hypoxia on Glycolytic Flux and Enzyme Activity in a Model of Solid Tumors: E FFECTS OF A NOXIA ON G LYCOLYSIS IN C ANCER Smith, Hannah; Board, Mary; Pellagatti, Andrea Journal of Cellular Biochemistry, Vol. 117, Issue 8 https://doi.org/10.1002/jcb.25488	journal	February 2016
Oridonin exerts anticancer effect on osteosarcoma by activating PPAR-γ and inhibiting Nrf2 pathway Lu, Ying; Sun, Yang; Zhu, Jianwei Cell Death & Disease, Vol. 9, Issue 1 https://doi.org/10.1038/s41419-017-0031-6	journal	January 2018
Triggering Fbw7-Mediated Proteasomal Degradation of c-Myc by Oridonin Induces Cell Growth Inhibition and Apoptosis Huang, Hui-Lin; Weng, Heng-You; Wang, Lu-Qin Molecular Cancer Therapeutics, Vol. 11, Issue 5 https://doi.org/10.1158/1535-7163.MCT-12-0066	journal	March 2012
PEPCK Coordinates the Regulation of Central Carbon Metabolism to Promote Cancer Cell Growth Montal, Emily D.; Dewi, Ruby; Bhalla, Kavita Molecular Cell, Vol. 60, Issue 4 https://doi.org/10.1016/j.molcel.2015.09.025	journal	November 2015
Oridonin induces autophagy via inhibition of glucose metabolism in p53-mutated colorectal cancer cells Yao, Zhuo; Xie, Fuhua; Li, Min Cell Death & Disease, Vol. 8, Issue 2 https://doi.org/10.1038/cddis.2017.35	journal	February 2017
Metabolic pathways promoting cancer cell survival and growth Boroughs, Lindsey K.; DeBerardinis, Ralph J. Nature Cell Biology, Vol. 17, Issue 4 https://doi.org/10.1038/ncb3124	journal	March 2015
Antitumor activity of the isodon diterpenoids: Structural requirements for the activity Fujita, E.; Nagao, Y.; Node, M. Experientia, Vol. 32, Issue 2 https://doi.org/10.1007/BF01937766	journal	February 1976
A Metal‐Organic Framework (MOF) Fenton Nanoagent‐Enabled Nanocatalytic Cancer Therapy in Synergy with Autophagy Inhibition Yang, Bowen; Ding, Li; Yao, Heliang Advanced Materials, Vol. 32, Issue 12 https://doi.org/10.1002/adma.201907152	journal	March 2020
Analysis and interpretation of transcriptomic data obtained from extended Warburg effect genes in patients with clear cell renal cell carcinoma Sanders, Edward; Diehl, Svenja Oncoscience, Vol. 2, Issue 2 https://doi.org/10.18632/oncoscience.128	journal	February 2015
Cancer statistics in China, 2015: Cancer Statistics in China, 2015 Chen, Wanqing; Zheng, Rongshou; Baade, Peter D. CA: A Cancer Journal for Clinicians, Vol. 66, Issue 2 https://doi.org/10.3322/caac.21338	journal	January 2016
Notch Signaling Activation in Cervical Cancer Cells Induces Cell Growth Arrest with the Involvement of the Nuclear Receptor NR4A2 Sun, Lichun; Liu, Mingqiu; Sun, Guang-Chun Journal of Cancer, Vol. 7, Issue 11 https://doi.org/10.7150/jca.15274	journal	January 2016
Oridonin‐induced mitochondria‐dependent apoptosis in esophageal cancer cells by inhibiting PI3K/AKT/mTOR and Ras/Raf pathways Jiang, Jin‐Huan; Pi, Jiang; Jin, Hua Journal of Cellular Biochemistry, Vol. 120, Issue 3 https://doi.org/10.1002/jcb.27654	journal	September 2018
Downregulation of PCK2 remodels tricarboxylic acid cycle in tumor-repopulating cells of melanoma Luo, S.; Li, Y.; Ma, R. Oncogene, Vol. 36, Issue 25 https://doi.org/10.1038/onc.2016.520	journal	February 2017
Gboxin is an oxidative phosphorylation inhibitor that targets glioblastoma Shi, Yufeng; Lim, S. Kyun; Liang, Qiren Nature, Vol. 567, Issue 7748 https://doi.org/10.1038/s41586-019-0993-x	journal	March 2019
Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries Bray, Freddie; Ferlay, Jacques; Soerjomataram, Isabelle CA: A Cancer Journal for Clinicians, Vol. 68, Issue 6 https://doi.org/10.3322/caac.21492	journal	September 2018
Glioblastoma and Other Malignant Gliomas: A Clinical Review Omuro, Antonio JAMA, Vol. 310, Issue 17 https://doi.org/10.1001/jama.2013.280319	journal	November 2013
Differential Site-Based Expression of Pentose Phosphate Pathway-Related Proteins among Breast Cancer Metastases Cha, Yoon Jin; Jung, Woo Hee; Koo, Ja Seung Disease Markers, Vol. 2017 https://doi.org/10.1155/2017/7062517	journal	January 2017
Oridonin inhibits hypoxia-induced epithelial–mesenchymal transition and cell migration by the hypoxia-inducible factor-1α/matrix metallopeptidase-9 signal pathway in gallbladder cancer Chen, Kunlun; Ye, Jianwen; Qi, Lei Anti-Cancer Drugs, Vol. 30, Issue 9 https://doi.org/10.1097/CAD.0000000000000797	journal	January 2019
Mitochondrial Phosphoenolpyruvate Carboxykinase (PEPCK-M) Is a Pro-survival, Endoplasmic Reticulum (ER) Stress Response Gene Involved in Tumor Cell Adaptation to Nutrient Availability Méndez-Lucas, Andrés; Hyroššová, Petra; Novellasdemunt, Laura Journal of Biological Chemistry, Vol. 289, Issue 32 https://doi.org/10.1074/jbc.M114.566927	journal	August 2014
CBTRUS Statistical Report: Primary Brain and Other Central Nervous System Tumors Diagnosed in the United States in 2011–2015 Ostrom, Quinn T.; Gittleman, Haley; Truitt, Gabrielle Neuro-Oncology, Vol. 20, Issue suppl_4 https://doi.org/10.1093/neuonc/noy131	journal	October 2018
Autophagy maintains tumour growth through circulating arginine Poillet-Perez, Laura; Xie, Xiaoqi; Zhan, Le Nature, Vol. 563, Issue 7732 https://doi.org/10.1038/s41586-018-0697-7	journal	November 2018
Hallmarks of Cancer: The Next Generation Hanahan, Douglas; Weinberg, Robert A. Cell, Vol. 144, Issue 5 https://doi.org/10.1016/j.cell.2011.02.013	journal	March 2011
Oridonin Sensitizes Cisplatin-Induced Apoptosis via AMPK/Akt/mTOR-Dependent Autophagosome Accumulation in A549 Cells Yang, Huahong; Gao, Yun; Fan, Xiaoye Frontiers in Oncology, Vol. 9 https://doi.org/10.3389/fonc.2019.00769	journal	August 2019
Upregulation of Cytosolic Phosphoenolpyruvate Carboxykinase Is a Critical Metabolic Event in Melanoma Cells That Repopulate Tumors Li, Yong; Luo, Shunqun; Ma, Ruihua Cancer Research, Vol. 75, Issue 7 https://doi.org/10.1158/0008-5472.CAN-14-2615	journal	February 2015
Targeting autophagy in cancer: Targeting Autophagy in Cancer Onorati, Angelique V.; Dyczynski, Matheus; Ojha, Rani Cancer, Vol. 124, Issue 16 https://doi.org/10.1002/cncr.31335	journal	April 2018
Oridonin induces apoptosis through the mitochondrial pathway in human gastric cancer SGC-7901 cells Gao, Shiyong; Tan, Huixin; Zhu, Nan International Journal of Oncology, Vol. 48, Issue 6 https://doi.org/10.3892/ijo.2016.3479	journal	April 2016
PCK2 activation mediates an adaptive response to glucose depletion in lung cancer Leithner, K.; Hrzenjak, A.; Trötzmüller, M. Oncogene, Vol. 34, Issue 8 https://doi.org/10.1038/onc.2014.47	journal	March 2014
Oridonin derivatives as potential anticancer drug candidates triggering apoptosis through mitochondrial pathway in the liver cancer cells Luo, Dongdong; Yi, Yujiao; Peng, Kai European Journal of Medicinal Chemistry, Vol. 178 https://doi.org/10.1016/j.ejmech.2019.06.006	journal	September 2019
Autophagy and multidrug resistance in cancer Li, Ying-Jie; Lei, Yu-He; Yao, Nan Chinese Journal of Cancer, Vol. 36, Issue 1 https://doi.org/10.1186/s40880-017-0219-2	journal	June 2017
Cancer statistics, 2018: Cancer Statistics, 2018 Siegel, Rebecca L.; Miller, Kimberly D.; Jemal, Ahmedin CA: A Cancer Journal for Clinicians, Vol. 68, Issue 1 https://doi.org/10.3322/caac.21442	journal	January 2018
Lomustine-temozolomide combination therapy versus standard temozolomide therapy in patients with newly diagnosed glioblastoma with methylated MGMT promoter (CeTeG/NOA–09): a randomised, open-label, phase 3 trial Herrlinger, Ulrich; Tzaridis, Theophilos; Mack, Frederic The Lancet, Vol. 393, Issue 10172 https://doi.org/10.1016/S0140-6736(18)31791-4	journal	February 2019
SnapShot: Cancer Metabolism Pathways Finley, Lydia W. S.; Zhang, Ji; Ye, Jiangbin Cell Metabolism, Vol. 17, Issue 3 https://doi.org/10.1016/j.cmet.2013.02.016	journal	March 2013
Expression of phosphoenolpyruvate carboxykinase linked to chemoradiation susceptibility of human colon cancer cells Park, Ji-Won; Kim, Seung Cheol; Kim, Won Ki BMC Cancer, Vol. 14, Issue 1 https://doi.org/10.1186/1471-2407-14-160	journal	March 2014
Mitochondrial Phosphoenolpyruvate Carboxykinase Regulates Metabolic Adaptation and Enables Glucose-Independent Tumor Growth Vincent, Emma E.; Sergushichev, Alexey; Griss, Takla Molecular Cell, Vol. 60, Issue 2 https://doi.org/10.1016/j.molcel.2015.08.013	journal	October 2015
PCK1 negatively regulates cell cycle progression and hepatoma cell proliferation via the AMPK/p27Kip1 axis Tuo, Lin; Xiang, Jin; Pan, Xuanming Journal of Experimental & Clinical Cancer Research, Vol. 38, Issue 1 https://doi.org/10.1186/s13046-019-1029-y	journal	February 2019
Dexamethasone inhibits the proliferation of tumor cells Wu, Yuantao; Xiab, Rui; Dai, Chungang Cancer Management and Research, Vol. Volume 11 https://doi.org/10.2147/CMAR.S187659	journal	January 2019
Oridonin attenuates carrageenan-induced pleurisy via activation of the KEAP-1/Nrf2 pathway and inhibition of the TXNIP/NLRP3 and NF-κB pathway in mice Yang, Huahong; Huang, Jingbo; Gao, Yanli Inflammopharmacology, Vol. 28, Issue 2 https://doi.org/10.1007/s10787-019-00644-y	journal	September 2019

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