A new facet of NDRG1 in pancreatic ductal adenocarcinoma: Suppression of glycolytic metabolism

Liu,Wensheng; Zhang,Bo; Hu,Qiangsheng; Qin,Yi; Xu,Wenyan; Shi,Si; Liang,Chen; Meng,Qingcai; Xiang,Jinfeng; Liang,Dingkong; Ji,Shunrong; Liu,Jiang; Hu,Pengfei; Liu,Liang; Liu,Chen; Long,Jiang; Ni,Quanxing; Yu,Xianjun; Xu,Jin

doi:10.3892/ijo.2017.3938

A new facet of NDRG1 in pancreatic ductal adenocarcinoma: Suppression of glycolytic metabolism

Authors:
- Wensheng Liu
- Bo Zhang
- Qiangsheng Hu
- Yi Qin
- Wenyan Xu
- Si Shi
- Chen Liang
- Qingcai Meng
- Jinfeng Xiang
- Dingkong Liang
- Shunrong Ji
- Jiang Liu
- Pengfei Hu
- Liang Liu
- Chen Liu
- Jiang Long
- Quanxing Ni
- Xianjun Yu
- Jin Xu
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Affiliations: Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, P.R. China, Pancreatic Cancer Institute, Fudan University, Shanghai, P.R. China
Published online on: March 28, 2017 https://doi.org/10.3892/ijo.2017.3938
Pages: 1792-1800

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Abstract

N-myc downstream-regulated gene 1 (NDRG1) is known as tumor/metastasis suppressor in a variety of cancers including pancreas, being involved in angiogenesis, cancer growth and metastasis. However, the precise molecular mechanism how NDRG1 exerts its inhibitory function in pancreatic cancer remains unclear. In this investigation, we demonstrated that K-Ras plays a vital role in modulating NDRG1 protein level in PDAC cancer cells in vitro, which is mediated through ERK signaling. Noteworthy, K-Ras downstream Akt/mTOR signaling is inhibited upon NDRG1 overexpression, resulting in decease of HIF1α level. Moreover, NDRG1 has a unique role in modulating cancer metabolism of pancreatic ductal adenocarcinoma (PDAC). The mechanism accounting for NDRG1 in modulating aerobic glycolysis, at least partly, relied on its regulation of glycolysis genes including GLUT1, HK2, LDHA and PDK1. Additionally, NDRG1 is shown to suppress the activity of HIF1α, which is responsible for regulation of glycolysis enzymes. The current study is the first to elucidate a unique facet of the potent tumor/metastasis suppressor NDRG1 in the regulation of PDAC glycolysis, leading to important insights into the mechanism by which NDRG1 exert inhibitory function in PDAC.

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1	Kamisawa T, Wood LD, Itoi T and Takaori K: Pancreatic cancer. Lancet. 388:73–85. 2016. View Article : Google Scholar : PubMed/NCBI
2	Le A, Rajeshkumar NV, Maitra A and Dang CV: Conceptual framework for cutting the pancreatic cancer fuel supply. Clin Cancer Res. 18:4285–4290. 2012. View Article : Google Scholar : PubMed/NCBI
3	Sousa CM and Kimmelman AC: The complex landscape of pancreatic cancer metabolism. Carcinogenesis. 35:1441–1450. 2014. View Article : Google Scholar : PubMed/NCBI
4	Cantor JR and Sabatini DM: Cancer cell metabolism: One hallmark, many faces. Cancer Discov. 2:881–898. 2012. View Article : Google Scholar : PubMed/NCBI
5	Ying H, Kimmelman AC, Lyssiotis CA, Hua S, Chu GC, Fletcher-Sananikone E, Locasale JW, Son J, Zhang H, Coloff JL, et al: Oncogenic Kras maintains pancreatic tumors through regulation of anabolic glucose metabolism. Cell. 149:656–670. 2012. View Article : Google Scholar : PubMed/NCBI
6	Meijer TW, Kaanders JH, Span PN and Bussink J: Targeting hypoxia, HIF-1, and tumor glucose metabolism to improve radiotherapy efficacy. Clin Cancer Res. 18:5585–5594. 2012. View Article : Google Scholar : PubMed/NCBI
7	Li B and Simon MC: Molecular Pathways: Targeting MYC-induced metabolic reprogramming and oncogenic stress in cancer. Clin Cancer Res. 19:5835–5841. 2013. View Article : Google Scholar : PubMed/NCBI
8	Miller DM, Thomas SD, Islam A, Muench D and Sedoris K: c-Myc and cancer metabolism. Clin Cancer Res. 18:5546–5553. 2012. View Article : Google Scholar : PubMed/NCBI
9	Smith SC and Theodorescu D: Learning therapeutic lessons from metastasis suppressor proteins. Nat Rev Cancer. 9:253–264. 2009. View Article : Google Scholar : PubMed/NCBI
10	Angst E, Dawson DW, Stroka D, Gloor B, Park J, Candinas D, Reber HA, Hines OJ and Eibl G: N-myc downstream regulated gene-1 expression correlates with reduced pancreatic cancer growth and increased apoptosis in vitro and in vivo. Surgery. 149:614–624. 2011. View Article : Google Scholar : PubMed/NCBI
11	Liu W, Yue F, Zheng M, Merlot A, Bae DH, Huang M, Lane D, Jansson P, Lui GY, Richardson V, et al: The proto-oncogene c-Src and its downstream signaling pathways are inhibited by the metastasis suppressor, NDRG1. Oncotarget. 6:8851–8874. 2015. View Article : Google Scholar : PubMed/NCBI
12	Jain S, Wang X, Chang CC, Ibarra-Drendall C, Wang H, Zhang Q, Brady SW, Li P, Zhao H, Dobbs J, et al: Src inhibition blocks c-Myc translation and glucose metabolism to prevent the development of breast cancer. Cancer Res. 75:4863–4875. 2015. View Article : Google Scholar : PubMed/NCBI
13	Ji S, Qin Y, Liang C, Huang R, Shi S, Liu J, Jin K, Liang D, Xu W, Zhang B, et al: FBW7 (F-box and WD repeat domain-containing 7) negatively regulates glucose metabolism by targeting the c-Myc/TXNIP (thioredoxin-binding protein) axis in pancreatic cancer. Clin Cancer Res. 22:3950–3960. 2016. View Article : Google Scholar : PubMed/NCBI
14	Emerling BM, Weinberg F, Liu JL, Mak TW and Chandel NS: PTEN regulates p300-dependent hypoxia-inducible factor 1 transcriptional activity through Forkhead transcription factor 3a (FOXO3a). Proc Natl Acad Sci USA. 105:2622–2627. 2008. View Article : Google Scholar : PubMed/NCBI
15	Kennedy AL, Adams PD and Morton JP: Ras, PI3K/Akt and senescence: Paradoxes provide clues for pancreatic cancer therapy. Small GTPases. 2:264–267. 2011. View Article : Google Scholar
16	Harada H, Itasaka S, Kizaka-Kondoh S, Shibuya K, Morinibu A, Shinomiya K and Hiraoka M: The Akt/mTOR pathway assures the synthesis of HIF-1alpha protein in a glucose- and reoxygenation-dependent manner in irradiated tumors. J Biol Chem. 284:5332–5342. 2009. View Article : Google Scholar
17	Denko NC: Hypoxia, HIF1 and glucose metabolism in the solid tumour. Nat Rev Cancer. 8:705–713. 2008. View Article : Google Scholar
18	Kurdistani SK, Arizti P, Reimer CL, Sugrue MM, Aaronson SA and Lee SW: Inhibition of tumor cell growth by RTP/rit42 and its responsiveness to p53 and DNA damage. Cancer Res. 58:4439–4444. 1998.PubMed/NCBI
19	Guan RJ, Ford HL, Fu Y, Li Y, Shaw LM and Pardee AB: Drg-1 as a differentiation-related, putative metastatic suppressor gene in human colon cancer. Cancer Res. 60:749–755. 2000.PubMed/NCBI
20	Bandyopadhyay S, Pai SK, Gross SC, Hirota S, Hosobe S, Miura K, Saito K, Commes T, Hayashi S, Watabe M, et al: The Drg-1 gene suppresses tumor metastasis in prostate cancer. Cancer Res. 63:1731–1736. 2003.PubMed/NCBI
21	Liu W, Xing F, Iiizumi-Gairani M, Okuda H, Watabe M, Pai SK, Pandey PR, Hirota S, Kobayashi A, Mo YY, et al: N-myc downstream regulated gene 1 modulates Wnt-β-catenin signalling and pleiotropically suppresses metastasis. EMBO Mol Med. 4:93–108. 2012. View Article : Google Scholar : PubMed/NCBI
22	Mann KM, Ying H, Juan J, Jenkins NA and Copeland NG: KRAS-related proteins in pancreatic cancer. Pharmacol Ther. 168:29–42. 2016. View Article : Google Scholar : PubMed/NCBI
23	Logsdon CD and Lu W: The significance of Ras activity in pancreatic cancer initiation. Int J Biol Sci. 12:338–346. 2016. View Article : Google Scholar : PubMed/NCBI
24	Jones RG and Thompson CB: Tumor suppressors and cell metabolism: A recipe for cancer growth. Genes Dev. 23:537–548. 2009. View Article : Google Scholar : PubMed/NCBI
25	Yun J, Rago C, Cheong I, Pagliarini R, Angenendt P, Rajagopalan H, Schmidt K, Willson JK, Markowitz S, Zhou S, et al: Glucose deprivation contributes to the development of KRAS pathway mutations in tumor cells. Science. 325:1555–1559. 2009. View Article : Google Scholar : PubMed/NCBI
26	Guo JY, Chen HY, Mathew R, Fan J, Strohecker AM, Karsli-Uzunbas G, Kamphorst JJ, Chen G, Lemons JM, Karantza V, et al: Activated Ras requires autophagy to maintain oxidative metabolism and tumorigenesis. Genes Dev. 25:460–470. 2011. View Article : Google Scholar : PubMed/NCBI
27	Hosoi F, Izumi H, Kawahara A, Murakami Y, Kinoshita H, Kage M, Nishio K, Kohno K, Kuwano M and Ono M: N-myc downstream regulated gene 1/Cap43 suppresses tumor growth and angiogenesis of pancreatic cancer through attenuation of inhibitor of kappaB kinase beta expression. Cancer Res. 69:4983–4991. 2009. View Article : Google Scholar : PubMed/NCBI
28	Guillaumond F, Leca J, Olivares O, Lavaut MN, Vidal N, Berthezène P, Dusetti NJ, Loncle C, Calvo E, Turrini O, et al: Strengthened glycolysis under hypoxia supports tumor symbiosis and hexosamine biosynthesis in pancreatic adenocarcinoma. Proc Natl Acad Sci USA. 110:3919–3924. 2013. View Article : Google Scholar : PubMed/NCBI
29	Sun HC, Qiu ZJ, Liu J, Sun J, Jiang T, Huang KJ, Yao M and Huang C: Expression of hypoxia-inducible factor-1α and associated proteins in pancreatic ductal adenocarcinoma and their impact on prognosis. Int J Oncol. 30:1359–1367. 2007.PubMed/NCBI
30	Maruyama Y, Ono M, Kawahara A, Yokoyama T, Basaki Y, Kage M, Aoyagi S, Kinoshita H and Kuwano M: Tumor growth suppression in pancreatic cancer by a putative metastasis suppressor gene Cap43/NDRG1/Drg-1 through modulation of angiogenesis. Cancer Res. 66:6233–6242. 2006. View Article : Google Scholar : PubMed/NCBI
31	Iyer NV, Kotch LE, Agani F, Leung SW, Laughner E, Wenger RH, Gassmann M, Gearhart JD, Lawler AM, Yu AY, et al: Cellular and developmental control of O2 homeostasis by hypoxia-inducible factor 1 alpha. Genes Dev. 12:149–162. 1998. View Article : Google Scholar : PubMed/NCBI
32	Chaika NV, Gebregiworgis T, Lewallen ME, Purohit V, Radhakrishnan P, Liu X, Zhang B, Mehla K, Brown RB, Caffrey T, et al: MUC1 mucin stabilizes and activates hypoxia-inducible factor 1 alpha to regulate metabolism in pancreatic cancer. Proc Natl Acad Sci USA. 109:13787–13792. 2012. View Article : Google Scholar : PubMed/NCBI
33	Chen C, Pore N, Behrooz A, Ismail-Beigi F and Maity A: Regulation of glut1 mRNA by hypoxia-inducible factor-1. Interaction between H-ras and hypoxia. J Biol Chem. 276:9519–9525. 2001. View Article : Google Scholar
34	Firth JD, Ebert BL and Ratcliffe PJ: Hypoxic regulation of lactate dehydrogenase A. Interaction between hypoxia-inducible factor 1 and cAMP response elements. J Biol Chem. 270:21021–21027. 1995. View Article : Google Scholar : PubMed/NCBI
35	Mathupala SP, Rempel A and Pedersen PL: Glucose catabolism in cancer cells: Identification and characterization of a marked activation response of the type II hexokinase gene to hypoxic conditions. J Biol Chem. 276:43407–43412. 2001. View Article : Google Scholar : PubMed/NCBI