AAED1 modulates proliferation and glycolysis in gastric cancer

Zhang,Beili; Wu,Jugang; Cai,Yantao; Luo,Meng; Wang,Bing; Gu,Yan

doi:10.3892/or.2018.6478

AAED1 modulates proliferation and glycolysis in gastric cancer

Authors:
- Beili Zhang
- Jugang Wu
- Yantao Cai
- Meng Luo
- Bing Wang
- Yan Gu
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Affiliations: Department of General Surgery, Shanghai Ninth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200011, P.R. China
Published online on: June 7, 2018 https://doi.org/10.3892/or.2018.6478
Pages: 1156-1164

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Abstract

Gastric cancer is one of the most common and lethal malignancies globally, especially in East Asia. Although significant progress has been made in the diagnosis and treatment of the disease, the overall survival rate remains unchanged at 20‑25%. Thus, there is an urgent need for a better understanding of the disease. Recent years have witnessed the critical roles of aberrant cancer cell metabolism in the maintenance of malignant properties of cancer cells, and targeting cancer cell metabolism has been regarded as a novel aspect in the development of treatments against cancer. In the present study, we identified a novel gene, AAED1 (AhpC/TSA antioxidant enzyme domain containing 1), which is upregulated in gastric cancer cells. By using lentivirus mediated transfection method, we silenced AAED1 expression and silencing of AAED1 inhibited cancer cell proliferation in vitro in gastric cancer cell lines, as demonstrated by cell viability and colony formation assay. Furthermore, we uncovered novel functions of AAED1 in regulating hypoxia inducible factor 1α (HIF1α) and the resultant aerobic glycolysis, which was measured by extracellular flux analysis. Collectively, the results of the present study uncovered novel markers that could identify the possible molecular mechanisms involved in gastric cancer.

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1	Siegel RL, Miller KD and Jemal A: Cancer statistics, 2017. CA Cancer J Clin. 67:7–30. 2017. View Article : Google Scholar : PubMed/NCBI
2	Fu DG: Epigenetic alterations in gastric cancer (Review). Mol Med Rep. 12:3223–3230. 2015. View Article : Google Scholar : PubMed/NCBI
3	Ushijima T and Sasako M: Focus on gastric cancer. Cancer Cell. 5:121–125. 2004. View Article : Google Scholar : PubMed/NCBI
4	Koppenol WH, Bounds PL and Dang CV: Otto Warburg's contributions to current concepts of cancer metabolism. Nat Rev Cancer. 11:325–337. 2011. View Article : Google Scholar : PubMed/NCBI
5	Hanahan D and Weinberg RA: Hallmarks of cancer: The next generation. Cell. 144:646–674. 2011. View Article : Google Scholar : PubMed/NCBI
6	Keith B, Johnson RS and Simon MC: HIF1α and HIF2α: Sibling rivalry in hypoxic tumour growth and progression. Nat Rev Cancer. 12:9–22. 2011. View Article : Google Scholar : PubMed/NCBI
7	Tennant DA, Durán RV and Gottlieb E: Targeting metabolic transformation for cancer therapy. Nat Rev Cancer. 10:267–277. 2010. View Article : Google Scholar : PubMed/NCBI
8	Denko NC: Hypoxia, HIF1 and glucose metabolism in the solid tumour. Nat Rev Cancer. 8:705–713. 2008. View Article : Google Scholar : PubMed/NCBI
9	Majmundar AJ, Wong WJ and Simon MC: Hypoxia-inducible factors and the response to hypoxic stress. Mol Cell. 40:294–309. 2010. View Article : Google Scholar : PubMed/NCBI
10	Rankin EB and Giaccia AJ: The role of hypoxia-inducible factors in tumorigenesis. Cell Death Differ. 15:678–685. 2008. View Article : Google Scholar : PubMed/NCBI
11	Xiao S and Zhou L: Gastric cancer: Metabolic and metabolomics perspectives (Review). Int J Oncol. 51:5–17. 2017. View Article : Google Scholar : PubMed/NCBI
12	Yang W, Ma J, Zhou W, Cao B, Zhou X, Yang Z, Zhang H, Zhao Q, Fan D and Hong L: Molecular mechanisms and theranostic potential of miRNAs in drug resistance of gastric cancer. Expert Opin Ther Targets. 21:1063–1075. 2017. View Article : Google Scholar : PubMed/NCBI
13	Jeong SM, Xiao C, Finley LW, Lahusen T, Souza AL, Pierce K, Li YH, Wang X, Laurent G, German NJ, et al: SIRT4 has tumor-suppressive activity and regulates the cellular metabolic response to DNA damage by inhibiting mitochondrial glutamine metabolism. Cancer Cell. 23:450–463. 2013. View Article : Google Scholar : PubMed/NCBI
14	Moffat J, Grueneberg DA, Yang X, Kim SY, Kloepfer AM, Hinkle G, Piqani B, Eisenhaure TM, Luo B, Grenier JK, et al: A lentiviral RNAi library for human and mouse genes applied to an arrayed viral high-content screen. Cell. 124:1283–1298. 2006. View Article : Google Scholar : PubMed/NCBI
15	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2^−ΔΔCT method. Methods. 25:402–408. 2001. View Article : Google Scholar : PubMed/NCBI
16	Zhang Z, Li J, Zheng H, Yu C, Chen J, Liu Z, Li M, Zeng M, Zhou F and Song L: Expression and cytoplasmic localization of SAM68 is a significant and independent prognostic marker for renal cell carcinoma. Cancer Epidemiol Biomarkers Prev. 18:2685–2693. 2009. View Article : Google Scholar : PubMed/NCBI
17	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
18	Bell EL, Emerling BM, Ricoult SJ and Guarente L: SirT3 suppresses hypoxia inducible factor 1α and tumor growth by inhibiting mitochondrial ROS production. Oncogene. 30:2986–2996. 2011. View Article : Google Scholar : PubMed/NCBI
19	Finley LW, Carracedo A, Lee J, Souza A, Egia A, Zhang J, Teruya-Feldstein J, Moreira PI, Cardoso SM, Clish CB, et al: SIRT3 opposes reprogramming of cancer cell metabolism through HIF1α destabilization. Cancer Cell. 19:416–428. 2011. View Article : Google Scholar : PubMed/NCBI
20	Adler V, Yin Z, Tew KD and Ronai Z: Role of redox potential and reactive oxygen species in stress signaling. Oncogene. 18:6104–6111. 1999. View Article : Google Scholar : PubMed/NCBI
21	Bell EL, Klimova TA, Eisenbart J, Schumacker PT and Chandel NS: Mitochondrial reactive oxygen species trigger hypoxia-inducible factor-dependent extension of the replicative life span during hypoxia. Mol Cell Biol. 27:5737–5745. 2007. View Article : Google Scholar : PubMed/NCBI
22	Chandel NS, McClintock DS, Feliciano CE, Wood TM, Melendez JA, Rodriguez AM and Schumacker PT: Reactive oxygen species generated at mitochondrial complex III stabilize hypoxia-inducible factor-1alpha during hypoxia: A mechanism of O2 sensing. J Biol Chem. 275:25130–25138. 2000. View Article : Google Scholar : PubMed/NCBI
23	Pore N, Jiang Z, Shu HK, Bernhard E, Kao GD and Maity A: Akt1 activation can augment hypoxia-inducible factor-1alpha expression by increasing protein translation through a mammalian target of rapamycin-independent pathway. Mol Cancer Res. 4:471–479. 2006. View Article : Google Scholar : PubMed/NCBI
24	Minet E, Arnould T, Michel G, Roland I, Mottet D, Raes M, Remacle J and Michiels C: ERK activation upon hypoxia: Involvement in HIF-1 activation. FEBS Lett. 468:53–58. 2000. View Article : Google Scholar : PubMed/NCBI
25	Cassavaugh JM, Hale SA, Wellman TL, Howe AK, Wong C and Lounsbury KM: Negative regulation of HIF-1α by an FBW7-mediated degradation pathway during hypoxia. J Cell Biochem. 112:3882–3890. 2011. View Article : Google Scholar : PubMed/NCBI
26	Lu K, Alcivar AL, Ma J, Foo TK, Zywea S, Mahdi A, Huo Y, Kensler TW, Gatza ML and Xia B: NRF2 induction supporting breast cancer cell survival is enabled by oxidative stress-induced DPP3-KEAP1 interaction. Cancer Res. 77:2881–2892. 2017. View Article : Google Scholar : PubMed/NCBI
27	Ngo HK, Kim DH, Cha YN, Na HK and Surh YJ: Nrf2 mutagenic activation drives hepatocarcinogenesis. Cancer Res. 77:4797–4808. 2017.PubMed/NCBI
28	Abu-Alainin W, Gana T, Liloglou T, Olayanju A, Barrera LN, Ferguson R, Campbell F, Andrews T, Goldring C, Kitteringham N, et al: UHRF1 regulation of the Keap1-Nrf2 pathway in pancreatic cancer contributes to oncogenesis. J Pathol. 238:423–433. 2016. View Article : Google Scholar : PubMed/NCBI
29	Hayes AJ, Skouras C, Haugk B and Charnley RM: Keap1-Nrf2 signalling in pancreatic cancer. Int J Biochem Cell Biol. 65:288–299. 2015. View Article : Google Scholar : PubMed/NCBI
30	Sporn MB and Liby KT: NRF2 and cancer: The good, the bad and the importance of context. Nat Rev Cancer. 12:564–571. 2012. View Article : Google Scholar : PubMed/NCBI
31	Cardone RA, Casavola V and Reshkin SJ: The role of disturbed pH dynamics and the Na⁺/H⁺ exchanger in metastasis. Nat Rev Cancer. 5:786–795. 2005. View Article : Google Scholar : PubMed/NCBI
32	Kato Y, Lambert CA, Colige AC, Mineur P, Noël A, Frankenne F, Foidart JM, Baba M, Hata R, Miyazaki K and Tsukuda M: Acidic extracellular pH induces matrix metalloproteinase-9 expression in mouse metastatic melanoma cells through the phospholipase D-mitogen-activated protein kinase signaling. J Biol Chem. 280:10938–10944. 2005. View Article : Google Scholar : PubMed/NCBI
33	Lu P, Takai K, Weaver VM and Werb Z: Extracellular matrix degradation and remodeling in development and disease. Cold Spring Harb Perspect Biol. 3:a0050582011. View Article : Google Scholar : PubMed/NCBI
34	Yu J, Li J, Chen Y, Cao W, Lu Y, Yang J and Xing E: Snail enhances glycolysis in the epithelial-mesenchymal transition process by targeting FBP1 in gastric cancer. Cell Physiol Biochem. 43:31–38. 2017. View Article : Google Scholar : PubMed/NCBI
35	Yang MH, Wu MZ, Chiou SH, Chen PM, Chang SY, Liu CJ, Teng SC and Wu KJ: Direct regulation of TWIST by HIF-1alpha promotes metastasis. Nat Cell Biol. 10:295–305. 2008. View Article : Google Scholar : PubMed/NCBI
36	Arany Z, Foo SY, Ma Y, Ruas JL, Bommi-Reddy A, Girnun G, Cooper M, Laznik D, Chinsomboon J, Rangwala SM, et al: HIF-independent regulation of VEGF and angiogenesis by the transcriptional coactivator PGC-1alpha. Nature. 451:1008–1012. 2008. View Article : Google Scholar : PubMed/NCBI