EGF receptor stimulation shifts breast cancer cell glucose metabolism toward glycolytic flux through PI3 kinase signaling


Autoři: Kyung-Ho Jung aff001;  Eun Jeong Lee aff003;  Jin Won Park aff001;  Jin Hee Lee aff001;  Seung Hwan Moon aff001;  Young Seok Cho aff001;  Kyung-Han Lee aff001
Působiště autorů: Department of Nuclear Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea aff001;  Department of Health Science and Technology, SAIHST, Sungkyunkwan University, Seoul, Korea aff002;  Department of Nuclear Medicine, Seoul Medical Center, Seoul, Korea aff003
Vyšlo v časopise: PLoS ONE 14(9)
Kategorie: Research Article
doi: https://doi.org/10.1371/journal.pone.0221294

Souhrn

Breast cancers that express epidermal growth factor (EGF) receptors (EGFRs) are associated with poor prognosis. Our group recently showed in breast cancer patients that EGFR expression is strongly correlated with high tumor uptake of the glucose analogue, 18F-fluorodeoxyglucose (FDG). Here, we explored the cellular mechanism and signaling pathways that can explain the relation between EGFR and breast cancer cell glucose metabolism. FDG uptake, lactate production and hexokinase (HK) activity were measured, and proliferation assays and western blots were performed. EGF stimulated an increase of FDG uptake in EGFR-positive T47D and MDA-MB-468 cells, but not in MCF-7 cells. In T47D cells, the effect was dose-dependent and was accompanied by increased lactate production, indicating a shift toward glycolytic flux. This metabolic response occurred through enhanced HK activity and upregulated glucose transporter 1 (GLUT1) expression. EGFR stimulation also increased T47D cell proliferation. Blocking EGFR activation with BIBX1382 or gefitinib completely abolished both FDG uptake and proliferation effects. EGFR stimulation induced MAP kinase (MAPK) and PI3 kinase (PI3K) activation. Increased cell proliferation by EGFR stimulation was completely abolished by MAPK inhibition with PD98059 or by PI3K inhibition with LY294002. Increased FDG uptake was also completely abrogated by PI3K inhibition but was uninfluenced by MAPK inhibition. These findings suggest that the association between breast tumor EGFR expression and high FDG uptake might be contributed by stimulation of the PI3K pathway downstream of EGFR activation. This was in contrast to EGFR-mediated cell proliferation that required MAPK as well as PI3K signaling.

Klíčová slova:

Biology and life sciences – Biochemistry – Metabolism – Carbohydrate metabolism – Glucose metabolism – Enzymology – Enzymes – Hexokinases – Proteins – Cell biology – Signal transduction – Cell signaling – Signaling cascades – MAPK signaling cascades – EGFR signaling – Cellular structures and organelles – Cell membranes – Membrane proteins – Cell processes – Cell proliferation – Medicine and health sciences – Oncology – Cancers and neoplasms – Breast tumors – Breast cancer – Physical sciences – Chemistry – Chemical compounds – Organic compounds – Carbohydrates – Monosaccharides – Glucose – Organic chemistry


Zdroje

1. Siegel RL, Miller KD, Jemal A. Cancer Statistics. CA Cancer J Clin. 2017;67:7–30. doi: 10.3322/caac.21387 28055103

2. AlFakeeh A, Brezden-Masley C. Overcoming endocrine resistance in hormone receptor-positive breast cancer. Curr Oncol. 2018;25: S18–S27. doi: 10.3747/co.25.3752 29910644

3. Reinert T, Barrios CH. Overall survival and progression-free survival with endocrine therapy for hormone receptor-positive, HER2-negative advanced breast cancer: review. Ther Adv Med Oncol. 2017;9:693–709. doi: 10.1177/1758834017728928 29344106

4. Masuda H, Zhang D, Bartholomeusz C, Doihara H, Hortobagyi GN, Ueno NT. Role of epidermal growth factor receptor in breast cancer. Breast Cancer Res Treat. 2012;1362:331–345. doi: 10.1007/s10549-012-2289-9 23073759

5. Gonzalez-Conchas GA, Rodriguez-Romo L, Hernandez-Barajas D, Gonzalez-Guerrero JF, Rodriguez-Fernandez IA, Verdines-Perez A, et al. Epidermal growth factor receptor overexpression and outcomes in early breast cancer: A systematic review and a meta-analysis. Cancer Treat Rev. 2018;62:1–8. doi: 10.1016/j.ctrv.2017.10.008 29126017

6. Levva S, Kotoula V, Kostopoulos I, Manousou K, Papadimitriou C, Papadopoulou K, et al. Prognostic Evaluation of Epidermal Growth Factor Receptor (EGFR) Genotype and Phenotype Parameters in Triple-negative Breast Cancers. Cancer Genomics Proteomics. 2017;14:181–195. doi: 10.21873/cgp.20030 28446533

7. Badve S, Dabbs DJ, Schnitt SJ, Baehner FL, Decker T, Eusebi V, et al. Basal-like and triple-negative breast cancers: a critical review with an emphasis on the implications for pathologists and oncologists. Mod Pathol. 2011;24:157–167. doi: 10.1038/modpathol.2010.200 21076464

8. Pons F, Duch J, Fuster D. Breast cancer therapy: the role of PET-CT in decision making. Q J Nucl Med Mol Imaging. 2009;53:210–223. 19293769

9. Oshida M, Uno K, Suzuki M, Nagashima T, Hashimoto H, Yagata H, et al. Predicting the prognoses of breast carcinoma patients with positron emission tomography using 2-deoxy-2-fluoro[18F]-D-glucose. Cancer. 1998;82:2227–2234. 9610703

10. Grover-McKay M, Walsh SA, Seftor EA, Thomas PA, Hendrix MJ. Role for glucose transporter 1 protein in human breast cancer. Pathol Oncol Res. 1998;4:115–120. 9654596

11. Smith TA, Titley JC, McCready VR. Proliferation is associated with 2-deoxy-D-[1-3H] glucose uptake by T47D breast tumour and SW480 and SW620 colonic tumour cells. Nucl Med Biol. 1998;25:481–485. 9720666

12. van der Hiel B, Pauwels EK, Stokkel MP. Positron emission tomography with 2-[18F]-fluoro-2-deoxy-D-glucose in oncology. Part IIIa: Therapy response monitoring in breast cancer, lymphoma and gliomas. J Cancer Res Clin Oncol. 2001;127:269–277. doi: 10.1007/s004320000191 11355141

13. Dehdashti F, Mortimer JE, Trinkaus K, Naughton MJ, Ellis M, Katzenellenbogen JA, et al. PET-based estradiol challenge as a predictive biomarker of response to endocrine therapy in women with estrogen-receptor-positive breast cancer. Breast Cancer Res Treat. 2009;113: 509–517. doi: 10.1007/s10549-008-9953-0 18327670

14. Lee J, Lee EJ, Moon SH, Kim S, Hyun SH, Cho YS, et al. Strong association of epidermal growth factor receptor status with breast cancer FDG uptake. Eur J Nucl Med Mol Imaging. 2017;44:1438–1447. doi: 10.1007/s00259-017-3705-5 28488029

15. Takahashi R, Hirata H, Tachibana I, Shimosegawa E, Inoue A, Nagatomo I, et al. Early [18F]fluorodeoxyglucose positron emission tomography at 2 days of gefitinib treatment predicts clinical outcome in patients with adenocarcinoma of the lung. Clin Cancer Res. 2012;18: 220–228. doi: 10.1158/1078-0432.CCR-11-0868 22019513

16. Di Fabio F, Pinto C, Rojas Llimpe FL, Fanti S, Castellucci P, Longobardi C, et al. The predictive value of 18F-FDG-PET early evaluation in patients with metastatic gastric adenocarcinoma treated with chemotherapy plus cetuximab. Gastric Cancer. 2007;10:221–227. doi: 10.1007/s10120-007-0438-3 18095077

17. Su H, Bodenstein C, Dumont RA, Seimbille Y, Dubinett S, Phelps ME, et al. Monitoring tumor glucose utilization by positron emission tomography for the prediction of treatment response to epidermal growth factor receptor kinase inhibitors. Clin Cancer Res. 2006;12:5659–5667. doi: 10.1158/1078-0432.CCR-06-0368 17020967

18. Hart S, Fischer OM, Prenzel N, Zwick-Wallasch E, Schneider M, Hennighausen L, et al. GPCR induced migration of breast carcinoma cells depends on both EGFR signal transactivation and EGFR independent pathways. Biol Chem. 2005;386:845–855. doi: 10.1515/BC.2005.099 16164409

19. Nicholson RI, McClelland RA, Gee JM, Manning DL, Cannon P, Robertson JF, et al. Epidermal growth factor receptor expression in breast cancer: association with response to endocrine therapy. Breast Cancer Res Treat. 1994;29:117–125. doi: 10.1007/bf00666187 7912565

20. Fan P, Wang J, Santen RJ, Yue W. Long-term treatment with tamoxifen facilitates translocation of estrogen receptor out of the nucleus and enhances its interaction with EGFR in MCF-7 breast cancer cells. Cancer Res. 2007;67:1352–1360. doi: 10.1158/0008-5472.CAN-06-1020 17283173

21. Batra S, Adekola KU, Rosen ST, Shanmugam M. Cancer metabolism as a therapeutic target. Oncology. 2013;27(5):460–467. 25184270

22. Vichai V, Kirtikara K. Sulforhodamine B colorimetric assay for cytotoxicity screening. Nature protocols. 2006;1:1112–1116. doi: 10.1038/nprot.2006.179 17406391

23. Zhou M, Sevilla L, Vallega G, Chen P, Palacin M, Zorzano A, et al. Insulin-dependent protein trafficking in skeletal muscle cells. Am J Physiol. 1998;275:E187–E196. doi: 10.1152/ajpendo.1998.275.2.E187 9688618

24. Vander Heiden MG, Cantley LC, Thompson CB. Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science. 2009;324:1029–1033. doi: 10.1126/science.1160809 19460998

25. Aloj L, Caraco C, Jagoda E, Eckelman WC, Neumann RD. Glut-1 and hexokinase expression: relationship with 2-fluoro-2-deoxy-D-glucose uptake in A431 and T47D cells in culture. Cancer Res. 1999;59: 4709–4714. 10493529

26. Nose A, Mori Y, Uchiyama-Tanaka Y, Kishimoto N, Maruyama K, Matsubara H, et al. Regulation of glucose transporter (GLUT1) gene expression by angiotensin II in mesangial cells: involvement of HB-EGF and EGF receptor transactivation. Hypertens Res. 2003;26: 67–73. 12661915

27. Sargeant RJ, Pâquet MR. Effect of insulin on the rates of synthesis and degradation of GLUT1 and GLUT4 glucose transporters in 3T3-L1 adipocytes. Biochem J. 1993;290: 913–919. doi: 10.1042/bj2900913 8457217

28. Illg D, Pette D. Turnover rates of hexokinase I, phosphofructokinase, pyruvate kinase and creatine kinase in slow-twitch soleus muscle and heart of the rabbit. Eur J Biochem. 1979;97:267–273. doi: 10.1111/j.1432-1033.1979.tb13111.x 157876

29. Gullick WJ. The epidermal growth factor system of ligands and receptors in cancer. Eur J Cancer. 2009;45:Suppl 1:205–210. doi: 10.1016/S0959-8049(09)70035-8 19775619

30. Lindsey S, Langhans SA. Epidermal growth factor signaling in transformed cells. Int Rev Cell Mol Biol. 2015;314:1–41. doi: 10.1016/bs.ircmb.2014.10.001 25619714

31. Wang H, Yao F, Luo S, Ma K, Liu M. Bai L, et al. A mutual activation loop between the Ca2+-activated chloride channel TMEM16A and EGFR/STAT3 signaling promotes breast cancer tumorigenesis. Cancer Lett. 2019;455:48–59. doi: 10.1016/j.canlet.2019.04.027 31042586

32. Kim S, Choi JH, Lim HI, Lee SK, Kim WW, Cho S, et al. EGF-induced MMP-9 expression is mediated by JAK3/ERK pathway, but not by the JAK3/STAT-3 pathway in a SKBR3 breast cancer cell line. Cell Signal. 2009;21:892–898. 19385051

33. Xu JW, Li QQ, Tao LL, Cheng YY, Yu J, Chen Q, et al. Involvement of EGFR in the promotion of malignant properties in multidrug resistant breast cancer cells. Int J Oncol. 2011;39:1501–1509. doi: 10.3892/ijo.2011.1143 21805028

34. Elbaz M, Nasser MW, Ravi J, Wani NA, Ahirwar DK, Zhao H, et al. Modulation of the tumor microenvironment and inhibition of EGF/EGFR pathway: Novel anti-tumor mechanisms of Cannabidiol in breast cancer. Mol Oncol. 2015;9:906–919. doi: 10.1016/j.molonc.2014.12.010 25660577

35. Guo B, Gao J, Zhan J, Zhang H. Kindlin-2 interacts with and stabilizes EGFR and is required for EGF-induced breast cancer cell migration. Cancer Lett. 2015;361:271–281. doi: 10.1016/j.canlet.2015.03.011 25790908

36. Enriori PJ, Vázquez SM, Chiauzzi V, Pérez C, Fischer CR, Gori JR, et al. Breast cyst fluids increase the proliferation of breast cell lines in correlation with their hormone and growth factor concentration. Clin Endocrinol (Oxf). 2006;64:20–28. doi: 10.1111/j.1365-2265.2005.02408.x 16402924

37. Kaplan O, Jaroszewski JW, Faustino PJ, Zugmaier G, Ennis BW, Lippman M, et al. Toxicity and effects of epidermal growth factor on glucose metabolism of MDA-468 human breast cancer cells. J Biol Chem. 1990;265:13641–13649. 2380179

38. Solca FF, Baum A, Langkopf E, Dahmann G, Heider KH, Himmelsbach F, et al. Inhibition of epidermal growth factor receptor activity by two pyrimidopyrimidine derivatives. J Pharmacol Exp Ther. 2004,311:502–509. doi: 10.1124/jpet.104.069138 15199094

39. Toulany M, Dittmann K, Baumann M, Rodemann HP. Radiosensitization of Ras-mutated human tumor cells in vitro by the specific EGF receptor antagonist BIBX1382BS. Radiother Oncol. 2005; 74:117–129. doi: 10.1016/j.radonc.2004.11.008 15734199

40. Toulany M, Kasten-Pisula U, Brammer I, Wang S, Chen J, Dittmann K, et al. Blockage of epidermal growth factor receptor-phosphatidylinositol 3-kinase-AKT signaling increases radiosensitivity of K-RAS mutated human tumor cells in vitro by affecting DNA repair. Clin Cancer Res. 2006;12:4119–4126. doi: 10.1158/1078-0432.CCR-05-2454 16818713

41. Ono M, Kuwano M. Molecular Mechanisms of Epidermal Growth Factor Receptor (EGFR) Activation and Response to Gefitinib and Other EGFR-Targeting Drugs. Clin Cancer Res. 2006;12:7242–7251. doi: 10.1158/1078-0432.CCR-06-0646 17189395

42. Zhu G, Fan Z, Ding M, Zhang H, Mu L, Ding Y, et al. An EGFR/PI3K/AKT axis promotes accumulation of the Rac1-GEF Tiam1 that is critical in EGFR-driven tumorigenesis. Oncogene. 2015;34:5971–5982. doi: 10.1038/onc.2015.45 25746002

43. Kyriakopoulou K, Kefali E, Piperigkou Z, Bassiony H, Karamanos NK. Advances in targeting epidermal growth factor receptor signaling pathway in mammary cancer. Cell Signal. 2018;51:99–109. doi: 10.1016/j.cellsig.2018.07.010 30071291

44. Prigent SA, Gullick WJ. Identification of c-erbB-3 binding sites for phosphatidylinositol 3'-kinase and SHC using an EGF receptor/c-erbB-3 chimera. EMBO J. 1994;13:2831–2841. 8026468

45. Citri A, Yarden Y. EGF-ERBB signaling: towards the systems level. Nat Rev Mol Cell Biol. 2006;7:505–516. doi: 10.1038/nrm1962 16829981

46. Nakai K, Hung MC, Yamaguchi H. A perspective on anti-EGFR therapies targeting triple-negative breast cancer. Am. J. Cancer Res. 2016;6:1609–1623. 27648353

47. Sánchez-Muñoz A, Pérez-Ruiz E, Jiménez B, Ribelles N, Márquez A, García-Ríos I, et al. Targeted therapy of metastatic breast cancer. Clin Transl Oncol. 2009;11:643–650. 19828406


Článek vyšel v časopise

PLOS One


2019 Číslo 9
Nejčtenější tento týden