GDNF regulates lipid metabolism and glioma growth through RET/ERK/HIF‑1/SREBP‑1

Yu,Zhi-Yun; Li,Hong-Jiang; Wang,Meng; Luo,Wen-Zheng; Xue,Ya-Ke

doi:10.3892/ijo.2022.5399

GDNF regulates lipid metabolism and glioma growth through RET/ERK/HIF‑1/SREBP‑1

Authors:
- Zhi-Yun Yu
- Hong-Jiang Li
- Meng Wang
- Wen-Zheng Luo
- Ya-Ke Xue
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Affiliations: Department of Neurosurgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450000, P.R. China
Published online on: July 27, 2022 https://doi.org/10.3892/ijo.2022.5399
Article Number: 109
Copyright: © Yu et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Cancer cells rewire their metabolism to meet the demands of growth and survival and this metabolic reprogramming has been recognized as an emerging hallmark of cancer. However, the respective mechanisms remain elusive and the contribution of aberrant lipid metabolism to the malignant phenotypes of glioma are unclear. The present study demonstrated that glial‑derived neurotrophic factor (GDNF) is highly expressed in glioma and associated with poor clinical outcomes. In addition, there was a significant correlation between GDNF/rearranged during transfection (RET)/ERK signaling and sterol regulatory element‑binding protein‑1 (SREBP‑1) expression in glioma cells. Pharmacological or genetic inhibition of GDNF‑induced RET/ERK activity downregulated SREBP‑1 expression and SREBP‑1‑mediated transcription of lipogenic genes. Additionally, GDNF regulated SREBP‑1 activity by promoting hypoxia‑inducible factor‑1α (HIF‑1α) mediated glucose absorption and hexosamine biosynthetic pathway mediated SREBP cleavage‑activating protein N‑glycosylation. In addition, the inhibition of SREBP‑1 reduced the in vitro GDNF‑induced glioma cell proliferation. The results elucidated the complex relationship between GDNF/RET/ERK signaling and dysregulated glycolipid‑metabolism, which shows great potential to uncover novel metabolic vulnerabilities and improve the efficacy of targeted therapies.

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1	Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B, Taphoorn MJ, Belanger K, Brandes AA, Marosi C, Bogdahn U, et al: Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med. 352:987–996. 2005.
2	Yu Z, Zhao G, Xie G, Zhao L, Chen Y, Yu H, Zhang Z, Li C and Li Y: Metformin and temozolomide act synergistically to inhibit growth of glioma cells and glioma stem cells in vitro and in vivo. Oncotarget. 6:32930–32943. 2015.
3	Yu Z, Xie G, Zhou G, Cheng Y, Zhang G, Yao G, Chen Y, Li Y and Zhao G: NVP-BEZ235, a novel dual PI3K-mTOR inhibitor displays anti-glioma activity and reduces chemoresistance to temozolomide in human glioma cells. Cancer Lett. 367:58–68. 2015.
4	Chen R, Smith-Cohn M, Cohen AL and Colman H: Glioma subclassifications and their clinical significance. Neurotherapeutics. 14:284–297. 2017.
5	Korshunov DA, Kondakova IV and Shashova EE: Modern perspective on metabolic reprogramming in malignant neoplasms. Biochemistry (Mosc). 84:1129–1142. 2019.
6	Tarrado-Castellarnau M, de Atauri P and Cascante M: Oncogenic regulation of tumor metabolic reprogramming. Oncotarget. 7:62726–62753. 2016.
7	Koundouros N and Poulogiannis G: Reprogramming of fatty acid metabolism in cancer. Br J Cancer. 122:4–22. 2020.
8	Cheng X, Li J and Guo D: SCAP/SREBPs are central players in lipid metabolism and novel metabolic targets in cancer therapy. Curr Top Med Chem. 18:484–493. 2018.
9	Williams KJ, Argus JP, Zhu Y, Wilks MQ, Marbois BN, York AG, Kidani Y, Pourzia AL, Akhavan D, Lisiero DN, et al: An essential requirement for the SCAP/SREBP signaling axis to protect cancer cells from lipotoxicity. Cancer Res. 73:2850–2862. 2013.
10	Nohturfft A, Yabe D, Goldstein JL, Brown MS and Espenshade PJ: Regulated step in cholesterol feedback localized to budding of SCAP from ER membranes. Cell. 102:315–323. 2000.
11	Mulligan LM: GDNF and the RET receptor in cancer: New insights and therapeutic potential. Front Physiol. 9:18732019.
12	Zhang L, Wang D, Han X, Tang F and Gao D: Mechanism of methylation and acetylation of high GDNF transcription in glioma cells: A review. Heliyon. 5:e019512019.
13	Shabtay-Orbach A, Amit M, Binenbaum Y, Na'ara S and Gil Z: Paracrine regulation of glioma cells invasion by astrocytes is mediated by glial-derived neurotrophic factor. Int J Cancer. 137:1012–1020. 2015.
14	Kawai K and Takahashi M: Intracellular RET signaling pathways activated by GDNF. Cell Tissue Res. 382:113–123. 2020.
15	Wiesenhofer B, Stockhammer G, Kostron H, Maier H, Hinterhuber H and Humpel C: Glial cell line-derived neurotrophic factor (GDNF) and its receptor (GFR-alpha 1) are strongly expressed in human gliomas. Acta Neuropathol. 99:131–137. 2000.
16	Zhang BL, Dong FL, Guo TW, Gu XH, Huang LY and Gao DS: MiRNAs Mediate GDNF-induced proliferation and migration of glioma cells. Cell Physiol Biochem. 44:1923–1938. 2017.
17	Liu XF, Tang CX, Zhang L, Tong SY, Wang Y, Abdulrahman AA, Ji GQ, Gao Y, Gao DS and Zhang BL: Down-Regulated CUEDC2 Increases GDNF expression by stabilizing CREB through reducing its ubiquitination in glioma. Neurochem Res. 45:2915–2925. 2020.
18	Ng WH, Wan GQ, Peng ZN and Too HP: Glial cell-line derived neurotrophic factor (GDNF) family of ligands confer chemoresistance in a ligand-specific fashion in malignant gliomas. J Clin Neurosci. 16:427–436. 2009.
19	Guo YJ, Pan WW, Liu SB, Shen ZF, Xu Y and Hu LL: ERK/MAPK signalling pathway and tumorigenesis. Exp Ther Med. 19:1997–2007. 2020.
20	Knebel B, Lehr S, Hartwig S, Haas J, Kaber G, Dicken HD, Susanto F, Bohne L, Jacob S, Nitzgen U, et al: Phosphorylation of sterol regulatory element-binding protein (SREBP)-1c by p38 kinases, ERK and JNK influences lipid metabolism and the secretome of human liver cell line HepG2. Arch Physiol Biochem. 120:216–227. 2014.
21	Liu H, Ma Q and Li J: High glucose promotes cell proliferation and enhances GDNF and RET expression in pancreatic cancer cells. Mol Cell Biochem. 347:95–101. 2011.
22	Ruan M, Liu M, Dong Q and Chen L: Iodide- and glucose-handling gene expression regulated by sorafenib or cabozantinib in papillary thyroid cancer. J Clin Endocrinol Metab. 100:1771–1779. 2015.
23	Louis DN, Perry A, Reifenberger G, von Deimling A, Figarella-Branger D, Cavenee WK, Ohgaki H, Wiestler OD, Kleihues P and Ellison DW: The 2016 World Health Organization classification of tumors of the central nervous system: A summary. Acta Neuropathol. 131:803–820. 2016.
24	Yu Z, Chen Y, Wang S, Li P, Zhou G and Yuan Y: Inhibition of NF-κB results in anti-glioma activity and reduces temozolomide-induced chemoresistance by down-regulating MGMT gene expression. Cancer Lett. 428:77–89. 2018.
25	Chou TC: Drug combination studies and their synergy quantification using the Chou-Talalay method. Cancer Res. 70:440–446. 2010.
26	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods. 25:402–408. 2001.
27	Nohturfft A, Brown MS and Goldstein JL: Topology of SREBP cleavage-activating protein, a polytopic membrane protein with a sterol-sensing domain. J Biol Chem. 273:17243–17250. 1998.
28	Cheng C, Ru P, Geng F, Liu J, Yoo JY, Wu X, Cheng X, Euthine V, Hu P, Guo JY, et al: Glucose-Mediated N-glycosylation of SCAP Is Essential for SREBP-1 activation and tumor growth. Cancer Cell. 28:569–581. 2015.
29	Akella NM, Ciraku L and Reginato MJ: Fueling the fire: Emerging role of the hexosamine biosynthetic pathway in cancer. BMC Biol. 17:522019.
30	Semenza GL: HIF-1: Upstream and downstream of cancer metabolism. Curr Opin Genet Dev. 20:51–56. 2010.
31	Kamisuki S, Mao Q, Abu-Elheiga L, Gu Z, Kugimiya A, Kwon Y, Shinohara T, Kawazoe Y, Sato S, Asakura K, et al: A small molecule that blocks fat synthesis by inhibiting the activation of SREBP. Chem Biol. 16:882–892. 2009.
32	Gholkar AA, Cheung K, Williams KJ, Lo YC, Hamideh SA, Nnebe C, Khuu C, Bensinger SJ and Torres JZ: Fatostatin inhibits cancer cell proliferation by affecting mitotic microtubule spindle assembly and cell division. J Biol Chem. 291:17001–17008. 2016.
33	Xue L, Qi H, Zhang H, Ding L, Huang Q, Zhao D, Wu BJ and Li X: Targeting SREBP-2-regulated mevalonate metabolism for cancer therapy. Front Oncol. 10:15102020.
34	Cheng C, Geng F, Cheng X and Guo D: Lipid metabolism reprogramming and its potential targets in cancer. Cancer Commun (Lond). 38:272018.
35	Ayanlaja AA, Zhang B, Ji G, Gao Y, Wang J, Kanwore K and Gao D: The reversible effects of glial cell line-derived neurotrophic factor (GDNF) in the human brain. Semin Cancer Biol. 53:212–222. 2018.
36	Mu P, Liu Y, Jiang S, Gao J, Sun S, Li L and Gao D: Glial cell line-derived neurotrophic factor alters lipid composition and protein distribution in MPP+-injured differentiated SH-SY5Y cells. J Cell Physiol. 235:9347–9360. 2020.
37	Yu ZQ, Zhang BL, Ren QX, Wang JC, Yu RT, Qu DW, Liu ZH, Xiong Y and Gao DS: Changes in transcriptional factor binding capacity resulting from promoter region methylation induce aberrantly high GDNF expression in human glioma. Mol Neurobiol. 48:571–580. 2013.
38	Cruceru ML, Enciu AM, Popa AC, Albulescu R, Neagu M, Tanase CP and Constantinescu SN: Signal transduction molecule patterns indicating potential glioblastoma therapy approaches. Onco Targets Ther. 6:1737–1749. 2013.
39	McPherson R and Gauthier A: Molecular regulation of SREBP function: The Insig-SCAP connection and isoform-specific modulation of lipid synthesis. Biochem Cell Biol. 82:201–211. 2004.
40	Zhu Z, Zhao X, Zhao L, Yang H, Liu L, Li J, Wu J, Yang F, Huang G and Liu J: p54(nrb)/NONO regulates lipid metabolism and breast cancer growth through SREBP-1A. Oncogene. 35:1399–1410. 2016.
41	Nagao A, Kobayashi M, Koyasu S, Chow CCT and Harada H: HIF-1-dependent reprogramming of glucose metabolic pathway of cancer cells and its therapeutic significance. Int J Mol Sci. 20:2382019.