Volume 7, Issue 5, October 2019, Page: 110-120
2-Deoxy-D-glucose Mediates Dihydrodiol Dehydrogenases Over-expression and Cisplatin Resistance in Human Cervical Cancer Cells
Jianli Chen, The Feinstein Institute for Medical Research, Northwell Health, Manhasset, New York, the United States; Department of Pathology, Staten Island University Hospital of Northwell Health, Staten Island, New York, the United States
Rong Wu, The Feinstein Institute for Medical Research, Northwell Health, Manhasset, New York, the United States; Department of Pathology, Staten Island University Hospital of Northwell Health, Staten Island, New York, the United States
John Zihou Chen, Jericho High School, Long Island, New York, the United States
Visitacion Pabicon, Department of Pathology, Staten Island University Hospital of Northwell Health, Staten Island, New York, the United States
Monika Wrzolek, Department of Pathology, Staten Island University Hospital of Northwell Health, Staten Island, New York, the United States
Fiona Simpkins, Gynecologic Oncology, Pennsylvania Perelman Center for Advanced Medicine, Philadelphia, Pennsylvania, the United States
Henry Simpkins, The Feinstein Institute for Medical Research, Northwell Health, Manhasset, New York, the United States; Department of Pathology, Staten Island University Hospital of Northwell Health, Staten Island, New York, the United States
Received: Sep. 30, 2019;       Accepted: Oct. 14, 2019;       Published: Oct. 23, 2019
DOI: 10.11648/j.ajbls.20190705.13      View  39      Downloads  16
Abstract
Dihydrodiol dehydrogenases (DDHs) belong to a superfamily of cytosolic NADP (H)-dependent oxidoreductases. The over-expression of DDHs induces cisplatin resistance. 2-Deoxy-D-glucose (2-DG), a glucose analogue, is currently being used as an anticancer reagent. In this study we investigated the effect of 2-DG on DDHs expression and cisplatin resistance in human cervical cancer 2008 and C13 cells. We employed RT-PCR to detect mRNA level of DDH1, DDH2, and DDH3 and western blotting for protein expression. The cisplatin resistance was investigated with MTT and colony formation assays. Apoptosis/necrosis and mitochondrial membrane potential analysis were evaluated with flow cytometry. The intracellular ROS regulation was evaluated with H2DCFDA probe. We used 2-DG resistant cells to demonstrate the effect of 2-DG on DDHs expression and cisplatin resistance. 2-DG significantly up-regulated the mRNA level and protein expression of DDH1, DDH2, and DDH3, which consequently increased cisplatin resistance as confirmed by MTT and colony formation assays. In the 2-DG-resistant cells, the apoptosis/necrosis percentage and intracellular ROS were significantly decreased. 2-DG itself could activate JNK. When treating the cells combined with cisplatin, 2-DG attenuated cisplatin-mediated JNK phosphorylation. 2-DG down-regulated wild-type p53 protein expression at lower 2-DG concentrations (1/2 IC50 and IC50) at 24-hour. Activated JNK attenuation and decreased p53 expression by 2-DG implied the underlying resistance mechanism. Our study highlighted that 2-DG, as an anticancer reagent currently, could be a two-side sword that also significantly inhibited apoptosis by up-regulating DDHs expression and consequently increased cisplatin resistance in the human cervical cancer cells we used.
Keywords
Cisplatin Resistance, Dihydrodiol Dehydrogenases, 2-Deoxy-D-glucose, Cancer Cells
To cite this article
Jianli Chen, Rong Wu, John Zihou Chen, Visitacion Pabicon, Monika Wrzolek, Fiona Simpkins, Henry Simpkins, 2-Deoxy-D-glucose Mediates Dihydrodiol Dehydrogenases Over-expression and Cisplatin Resistance in Human Cervical Cancer Cells, American Journal of Biomedical and Life Sciences. Vol. 7, No. 5, 2019, pp. 110-120. doi: 10.11648/j.ajbls.20190705.13
Copyright
Copyright © 2019 Authors retain the copyright of this article.
This article is an open access article distributed under the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Reference
[1]
Kang HT, Hwang ES. 2-Deoxyglucose: An anticancer and antiviral therapeutic, but not anymore a low glucose mimetic. Life Sciences 2006; 78: 1392-1399.
[2]
Maher JC, Wangpaichitr M, Savaraj N, Kurtoglu M, Lampidis TJ. Hypoxia-inducible factor-1 confers resistance to the glycolytic inhibitor 2-deoxy-D-glucose. Mol Cancer Ther 2007; 6: 732-741.
[3]
Dwarakanath BS, Singh D, Banerji AK, Sarin R, Venkataramana NK, Jalali R, Vishwanath PN, Mohanti BK, Tripathi RP, Kalia VK, Jain V. Clinical studies for improving radiotherapy with 2-deoxy-D-glucose: present status and future prospects. J Cancer Res Ther 2009; 1: S21-26.
[4]
Ledoux S, Yang R, Friedlander G, Laouari D. Glucose depletion enhances P-glycoprotein expression in hepatoma cells: role of endoplasmic reticulum stress response. Cancer Res 2003; 63: 7284-7290.
[5]
Qian X, Xu W, Xu J, Shi Q, Li J, Weng Y, Jiang Z, Feng L, Wang X, Zhou J, Jin H. Enolase 1 stimulates glycolysis to promote chemoresistance in gastric cancer. Oncotarget 2017; 8: 47691-47708.
[6]
Park GB, Chung YH, Kim D. 2-Deoxy-D-glucose suppresses the migration and reverses the drug resistance of colon cancer cells through ADAM expression regulation. Anticancer Drugs 2017; 28: 410-420.
[7]
Xue C, Wang C, Sun Y, Meng Q, Liu Z, Huo X, Sun P, Sun H, Ma X, Ma X, Peng J, Liu K. Targeting P-glycoprotein function, p53 and energy metabolism: Combination of metformin and 2-deoxyglucose reverses the multidrug resistance of MCF-7/Dox cells to doxorubicin. Oncotarget 2017; 8: 8622-8632.
[8]
Xue C, Wang C, Liu Q, Meng Q, Sun H, Huo X, Ma X, Liu Z, Ma X, Peng J, Liu K. Targeting P-glycoprotein expression and cancer cell energy metabolism: combination of metformin and 2-deoxyglucose reverses the multidrug resistance of K562/Dox cells to doxorubicin. Tumour Biol 2016; 37: 8587-8597.
[9]
Pang YY, Wang T, Chen FY, Wu YL, Shao X, Xiao F, Huang HH, Zhong H, Zhong JH. Glycolytic inhibitor 2-deoxy-d-glucose suppresses cell proliferation and enhances methylprednisolone sensitivity in non-Hodgkin lymphoma cells through down-regulation of HIF-1α and c-MYC. Leuk Lymphoma 2015; 56: 1821-1830.
[10]
Xu Y, Wang Q, Zhang L, Zheng M. 2-Deoxy-D-glucose enhances TRAIL-induced apoptosis in human gastric cancer cells through downregulating JNK-mediated cytoprotective autophagy. Cancer Chemother Pharmacol 2018; 81: 555-564.
[11]
Pawłowski KM, Mucha J, Majchrzak K, Motyl T, Król M. Expression and role of PGP, BCRP, MRP1 and MRP3 in multidrug resistance of canine mammary cancer cells. BMC Vet Res 2013; 9: 119.
[12]
Deng HB, Adikari M, Parekh HK, Simpkins H. Increased expression of dihydrodiol dehydrogenase induces resistance to cisplatin in human cervicalcarcinoma cells. J Biol Chem 2002; 277: 15035-15043.
[13]
Chen J, Adikari M, Pallai R, Parekh HK, Simpkins H. Dihydrodiol dehydrogenase regulates the generation of reactive oxygen species and the development of cisplatin resistance in human cervicalcarcinoma cells. Cancer Chemother. Pharmacol 2008; 61: 979-987.
[14]
Chen J, Solomides C, Parekh H, Simpkins F, Simpkins H. Cisplatin resistance in human cervical, ovarian and lung cancer cells. Cancer Chemother Pharmacol 2015; 75: 1217-1227.
[15]
Deng HB, Adikari M, Parekh HK, Simpkins H. Ubiquitous induction of resistance to platinum drugs in human ovarian, cervical, germ cell and lung carcinoma tumor cells overexpressing isoforms 1 and 2 of dihydrodriol dehydrogenase. Cancer Chemother Pharmacol 2004; 54: 301-307.
[16]
Chen YJ, Yuan GC, Chan KC, et al. over-expression of dihydrodiol dehydrogenase is associated with cisplatin-based chemotherapy resistance in cervical cancer patients. Gynecol Oncol 2005; 97: 110-117.
[17]
Hsu NY, Ho HC, Chow KC, Lin TY, Shih CS, Wang LS, Tsai CM. over-expression of dihydrodiol dehydrogenase as a prognostic marker of non-small cell lung cancer. Cancer Res 2001; 61: 2727-2731.
[18]
Parekh HK, Simpkins H. The differential expression of cytokeratin 18 in cisplatin-sensitive and resistant human cervicaladenocarcinoma cells and its association with drug sensitivity. Cancer Res 1995; 55: 5203-5206.
[19]
Simons AL, Ahmad IM, Mattson DM, Dornfeld KJ, Spitz DR. 2-Deoxy-D-glucose combined with cisplatin enhances cytotoxicity via metabolic oxidative stress in human head and neck cancer cells. Cancer Res 2007; 67: 3364-3370.
[20]
Mingo-Sion AM, Marietta PM, Koller E, Wolf DM, Van Den Berg CL. Inhibition of JNK reduces G2/M transit independent of p53, leading to endoreduplication, decreased proliferation, and apoptosis in breast cancer cells. Oncogene 2004; 23: 596-604.
[21]
Shankar E, Basu C, Adkins B, Siede W, Basu A. NSC109268 potentiates cisplatin-induced cell death in a p53-independent manner. J Mol Signal 2010; 5: 4-11.
[22]
Gebauer A, Mirakhur B, Nguyen A, Shue SK, H. Simpkins H, Dhanasekaran N. Cisplatin resistance involving the defective processing of MEKKI in human cervicaladenocarcinoma 2008/C13 cells. Int Jnl Oncology 2000; 16: 321-325.
[23]
Fuchs SY, Adler V, Buschmann T, Yin Z, Wu X, Jones SN, Ronai Z. JNK targets p53 ubiquitination and degradation in nonstressed cells. Genes Dev 1998; 12: 2658-2663.
[24]
Ahmad IM, Abdalla MY, Aykin-Burns N, Simons AL, Oberley LW, Domann FE, Spitz DR. 2-Deoxyglucose combined with wild-type p53 over-expression enhances cytotoxicity in human prostate cancer cells via oxidative stress. Free Radic Biol Med 2008; 44: 826-834.
[25]
Xi H, Kurtoglu M, Liu H, Wangpaichitr M, You M, Liu X, Savaraj N, Lampidis TJ.2-Deoxy-D-glucose activates autophagy via endoplasmic reticulum stress rather than ATP depletion. Cancer Chemother Pharmacol 2011; 67: 899-910.
[26]
Lee AS. GRP78 induction in cancer: therapeutic and prognostic implications. Cancer Res 2007; 67: 3496-3499.
[27]
Ni M, Zhang Y, Lee AS. Beyond the endoplasmic reticulum: atypical GRP78 in cell viability, signalling and therapeutic targeting. Biochem J 2011; 434: 181-188.
[28]
Pallai R, H Simpkins, Jianli Chen, HK Parekh. Nuclear Factor Y regulates the transcription of the human aldoketoreductase AKR1C1 gene. Gene 2010; 459: 11-23.
[29]
Chan DW, Liu VW, Tsao GS, Yao KM, Furukawa T, Chan KK, Ngan HY. Loss of MKP3 mediated by oxidative stress enhances tumorigenicity and chemoresistance of cervical cancer cells. Carcinogenesis 2008; 29: 1742-50.
[30]
Deshpande VS, Kehrer James P. Mechanisms of N-acetylcysteine-driven enhancement of MK886-induced apoptosis. Cell Bil Toxicol 2006; 22: 303-311.
[31]
Rakshit S, Bagchi J, Mandal L, Paul K, et al. N-acetyl cysteine enhances imatinib-induced apoptosis of Bcr-Abl+ cells by endothelial nitric oxide synthase-mediated production of nitric oxide. Apoptosis 2009; 14: 298-308.
Browse journals by subject