AI Chat Paper
Note: Please note that the following content is generated by AMiner AI. SciOpen does not take any responsibility related to this content.
{{lang === 'zh_CN' ? '文章概述' : 'Summary'}}
{{lang === 'en_US' ? '中' : 'Eng'}}
Chat more with AI
PDF (4.2 MB)
Collect
Submit Manuscript AI Chat Paper
Show Outline
Outline
Show full outline
Hide outline
Outline
Show full outline
Hide outline
Full Length Article | Open Access

Targeting fructose metabolism by glucose transporter 5 regulation in human cholangiocarcinoma

Nattawan SuwannakulaNapat ArmartmuntreebRaynoo ThananbKaoru MidorikawaaTetsuo KoncShinji OikawaaHatasu KobayashiaNing MadShosuke KawanishieMariko Murataa( )
Department of Environmental and Molecular Medicine, Mie University Graduate School of Medicine, Tsu, Mie 514-8507, Japan
Department of Biochemistry, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand
Laboratory of Functional Genomics, Graduate School of Bioscience, Nagahama Institute of Bioscience and Technology, Nagahama, Shiga 526-0829, Japan
Graduate School of Health Science, Suzuka University of Medical Science, Suzuka, Mie 513-8670, Japan
Faculty of Pharmaceutical Sciences, Suzuka University of Medical Science, Suzuka, Mie 513-8670, Japan

Peer review under responsibility of Chongqing Medical University.

Show Author Information

Abstract

Alterations in cellular metabolism may contribute to tumor proliferation and survival. Upregulation of the facilitative glucose transporter (GLUT) plays a key role in promoting cancer. GLUT5 mediates modulation of fructose utilization, and its overexpression has been associated with poor prognosis in several cancers. However, its metabolic regulation remains poorly understood. Here, we demonstrated elevated GLUT5 expression in human cholangiocarcinoma (CCA), using RNA sequencing data from samples of human tissues and cell lines, as compared to normal liver tissues or a cholangiocyte cell line. Cells exhibiting high-expression of GLUT5 showed increased rates of cell proliferation and ATP production, particularly in a fructose-supplemented medium. In contrast, GLUT5 silencing attenuated cell proliferation, ATP production, cell migration/invasion, and improved epithelial–mesenchymal transition (EMT) balance. Correspondingly, fructose consumption increased tumor growth in a nude mouse xenograft model, and GLUT5 silencing suppressed growth, supporting the tumor-inhibitory effect of GLUT5 downregulation. Furthermore, in the metabolic pathways of fructolysis-Warburg effect, the expression levels of relative downstream genes, including ketohexokinase (KHK), aldolase B (ALDOB), lactate dehydrogenase A (LDHA), and monocarboxylate transporter 4 (MCT4), as well as hypoxia-inducible factor 1 alpha (HIF1A), were altered in a GLUT5 expression-dependent manner. Taken together, these findings indicate that GLUT5 could be a potential target for CCA therapeutic approach via metabolic regulation.

References

1

Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144(5):646-674.

2

Warburg O. On the origin of cancer cells. Science. 1956;123(3191):309-314.

3

de la Cruz-López KG, Castro-Muñoz LJ, Reyes-Hernández DO, García-Carrancá A, Manzo-Merino J. Lactate in the regulation of tumor microenvironment and therapeutic approaches. Front Oncol. 2019;9:1143.

4

Jang M, Kim SS, Lee J. Cancer cell metabolism: implications for therapeutic targets. Exp Mol Med. 2013;45(10):e45.

5

Krause N, Wegner A. Fructose metabolism in cancer. Cells. 2020;9(12):2635.

6

Taskinen MR, Packard CJ, Borén J. Dietary fructose and the metabolic syndrome. Nutrients. 2019;11(9):1987.

7

Charrez B, Qiao L, Hebbard L. The role of fructose in metabolism and cancer. Horm Mol Biol Clin Investig. 2015;22(2):79-89.

8

Weng Y, Zhu J, Chen Z, Fu J, Zhang F. Fructose fuels lung adenocarcinoma through GLUT5. Cell Death Dis. 2018;9(5):557.

9

Liu H, Huang D, McArthur DL, Boros LG, Nissen N, Heaney AP. Fructose induces transketolase flux to promote pancreatic cancer growth. Cancer Res. 2010;70(15):6368-6376.

10

Zhao FQ, Keating AF. Functional properties and genomics of glucose transporters. Curr Genomics. 2007;8(2):113-128.

11

Zwarts I, van Zutphen T, Kruit JK, et al. Identification of the fructose transporter GLUT5 (SLC2A5) as a novel target of nuclear receptor LXR. Sci Rep. 2019;9(1):9299.

12

Fan X, Liu H, Liu M, Wang Y, Qiu L, Cui Y. Increased utilization of fructose has a positive effect on the development of breast cancer. PeerJ. 2017;5:e3804.

13

Weng Y, Fan X, Bai Y, et al. SLC2A5 promotes lung adenocarcinoma cell growth and metastasis by enhancing fructose utilization. Cell Death Discov. 2018;4:38.

14

Suwannakul N, Ma N, Midorikawa K, et al. CD44v9 induces stem cell-like phenotypes in human cholangiocarcinoma. Front Cell Dev Biol. 2020;8:417.

15

Nakagawa T, Lanaspa MA, Millan IS, et al. Fructose contributes to the Warburg effect for cancer growth. Cancer Metab. 2020;8:16.

16

Samuel VT. Fructose induced lipogenesis: from sugar to fat to insulin resistance. Trends Endocrinol Metabol. 2011;22(2):60-65.

17

Strober JW, Brady MJ. Dietary fructose consumption and triple-negative breast cancer incidence. Front Endocrinol. 2019;10:367.

18

Ozawa T, Maehara N, Kai T, Arai S, Miyazaki T. Dietary fructose-induced hepatocellular carcinoma development manifested in mice lacking apoptosis inhibitor of macrophage (AIM). Genes Cells. 2016;21(12):1320-1332.

19

Hussar P, Popovska-Percinic F, Blagoevska K, Järveots T, Dūrītis I. Immunohistochemical study of glucose transporter GLUT-5 in duodenal epithelium in norm and in T-2 mycotoxicosis. Foods. 2020;9(7):849.

20

Chen WL, Jin X, Wang M, et al. GLUT5-mediated fructose utilization drives lung cancer growth by stimulating fatty acid synthesis and AMPK/mTORC1 signaling. JCI Insight. 2020;5(3):e131596.

21

Jin X, Liang Y, Liu D, et al. An essential role for GLUT5-mediated fructose utilization in exacerbating the malignancy of clear cell renal cell carcinoma. Cell Biol Toxicol. 2019;35(5):471-483.

22

Jin C, Gong X, Shang Y. GLUT5 increases fructose utilization in ovarian cancer. Onco Targets Ther. 2019;12:5425-5436.

23

Chen WL, Wang YY, Zhao A, et al. Enhanced fructose utilization mediated by SLC2A5 is a unique metabolic feature of acute myeloid leukemia with therapeutic potential. Cancer Cell. 2016;30(5):779-791.

24
MellorKMBellJRWendtIRDavidoffAJRitchieRHDelbridgeLMFructose modulates cardiomyocyte excitation-contraction coupling and Ca2+ handling in vitroPLoS One201169e2520410.1371/journal.pone.0025204

Mellor KM, Bell JR, Wendt IR, Davidoff AJ, Ritchie RH, Delbridge LM. Fructose modulates cardiomyocyte excitation-contraction coupling and Ca2+ handling in vitro. PLoS One. 2011;6(9):e25204.

25

Barone S, Fussell SL, Singh AK, et al. Slc2a5 (Glut 5) is essential for the absorption of fructose in the intestine and generation of fructose-induced hypertension. J Biol Chem. 2009;284(8):5056-5066.

26

Włodarczyk J, Włodarczyk M, Zielińska M, Jędrzejczak B, Dziki Ł, Fichna J. Blockade of fructose transporter protein GLUT5 inhibits proliferation of colon cancer cells: proof of concept for a new class of anti-tumor therapeutics. Pharmacol Rep. 2021;73(3):939-945.

27

Park GB, Jeong JY, Kim D. GLUT5 regulation by AKT1/3-miR-125b-5p downregulation induces migratory activity and drug resistance in TLR-modified colorectal cancer cells. Carcinogenesis. 2020;41(10):1329-1340.

28

Merino B, Fernández-Díaz CM, Cózar-Castellano I, Perdomo G. Intestinal fructose and glucose metabolism in health and disease. Nutrients. 2019;12(1):94.

29

Danhier P, Bański P, Payen VL, et al. Cancer metabolism in space and time: beyond the Warburg effect. Biochim Biophys Acta Bioenerg. 2017;1858(8):556-572.

30

Cai Q, Lin T, Kamarajugadda S, Lu J. Regulation of glycolysis and the Warburg effect by estrogen-related receptors. Oncogene. 2013;32(16):2079-2086.

31

Jiang F, Ma S, Xue Y, Hou J, Zhang Y. LDH-A promotes malignant progression via activation of epithelial-to-mesenchymal transition and conferring stemness in muscle-invasive bladder cancer. Biochem Biophys Res Commun. 2016;469(4):985-992.

32

Kim HK, Lee I, Bang H, et al. MCT4 expression is a potential therapeutic target in colorectal cancer with peritoneal carcinomatosis. Mol Cancer Ther. 2018;17(4):838-848.

33

Xiao S, Zhu H, Shi Y, Wu Z, Wu H, Xie M. Prognostic and predictive value of monocarboxylate transporter 4 in patients with breast cancer. Oncol Lett. 2020;20(3):2143-2152.

34

Gotanda Y, Akagi Y, Kawahara A, et al. Expression of monocarboxylate transporter (MCT)-4 in colorectal cancer and its role: MCT4 contributes to the growth of colorectal cancer with vascular endothelial growth factor. Anticancer Res. 2013;33(7):2941-2947.

35

Kim Y, Choi JW, Lee JH, Kim YS. Expression of lactate/H⁺ symporters MCT1 and MCT4 and their chaperone CD147 predicts tumor progression in clear cell renal cell carcinoma: immunohistochemical and The Cancer Genome Atlas data analyses. Hum Pathol. 2015;46(1):104-112.

36

Chang L, Fang S, Gu W. The molecular mechanism of metabolic remodeling in lung cancer. J Cancer. 2020;11(6):1403-1411.

37

Cai H, Li J, Zhang Y, et al. LDHA promotes oral squamous cell carcinoma progression through facilitating glycolysis and epithelial–mesenchymal transition. Front Oncol. 2019;9:1446.

38

Peppicelli S, Bianchini F, Calorini L. Extracellular acidity, a “reappreciated” trait of tumor environment driving malignancy: perspectives in diagnosis and therapy. Cancer Metastasis Rev. 2014;33(2–3):823-832.

39

Jin X, Dai L, Ma Y, Wang J, Liu Z. Implications of HIF-1α in the tumorigenesis and progression of pancreatic cancer. Cancer Cell Int. 2020;20:273.

40

Moldogazieva NT, Mokhosoev IM, Terentiev AA. Metabolic heterogeneity of cancer cells: an interplay between HIF-1, GLUTs, and AMPK. Cancers (Basel). 2020;12(4):862.

41

Serganova I, Cohen IJ, Vemuri K, et al. LDH-A regulates the tumor microenvironment via HIF-signaling and modulates the immune response. PLoS One. 2018;13(9):e0203965.

42

Ullah MS, Davies AJ, Halestrap AP. The plasma membrane lactate transporter MCT4, but not MCT1, is up-regulated by hypoxia through a HIF-1 alpha-dependent mechanism. J Biol Chem. 2006;281(14):9030-9037.

43

Zhang L, Li S. Lactic acid promotes macrophage polarization through MCT-HIF1α signaling in gastric cancer. Exp Cell Res. 2020;388(2):111846.

44

Sadlecki P, Bodnar M, Grabiec M, et al. The role of Hypoxia-inducible factor-1 α , glucose transporter-1, (GLUT-1) and carbon anhydrase IX in endometrial cancer patients. Biomed Res Int. 2014;2014:616850.

45

Hayashi M, Sakata M, Takeda T, et al. Induction of glucose transporter 1 expression through hypoxia-inducible factor 1 alpha under hypoxic conditions in trophoblast-derived cells. J Endocrinol. 2004;183(1):145-154.

46

Yasuda M, Miyazawa M, Fujita M, et al. Expression of hypoxia inducible factor-1 alpha (HIF-1alpha) and glucose transporter-1 (GLUT-1) in ovarian adenocarcinomas: difference in hypoxic status depending on histological character. Oncol Rep. 2008;19(1):111-116.

47

Hao LS, Liu Q, Tian C, et al. Correlation and expression analysis of hypoxia-inducible factor 1α, glucose transporter 1 and lactate dehydrogenase 5 in human gastric cancer. Oncol Lett. 2019;18(2):1431-1441.

48

Yu J, Li J, Zhang S, et al. IGF-1 induces hypoxia-inducible factor 1α-mediated GLUT3 expression through PI3K/Akt/mTOR dependent pathways in PC12 cells. Brain Res. 2012;1430:18-24.

49

Hamann I, Krys D, Glubrecht D, et al. Expression and function of hexose transporters GLUT1, GLUT2, and GLUT5 in breast cancer-effects of hypoxia. FASEB J. 2018;32(9):5104-5118.

Genes & Diseases
Pages 1727-1741
Cite this article:
Suwannakul N, Armartmuntree N, Thanan R, et al. Targeting fructose metabolism by glucose transporter 5 regulation in human cholangiocarcinoma. Genes & Diseases, 2022, 9(6): 1727-1741. https://doi.org/10.1016/j.gendis.2021.09.002

534

Views

11

Downloads

13

Crossref

13

Web of Science

13

Scopus

1

CSCD

Altmetrics

Received: 21 May 2021
Revised: 26 August 2021
Accepted: 11 September 2021
Published: 02 October 2021
© 2021, Chongqing Medical University.

This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Return