Endocrinol Metab.  2020 Jun;35(2):227-236. 10.3803/EnM.2020.35.2.227.

Amino Acid Transporters as Potential Therapeutic Targets in Thyroid Cancer

• Enomoto K
• Hotomi M

• KMID: 2503253
• DOI: http://doi.org/10.3803/EnM.2020.35.2.227

Abstract

Thyroid cancer cells have a high amino acid demand for proliferation, invasion, and metastasis. Amino acids are taken up by thyroid cancer cells, both thyroid follicular cell and thyroid parafollicular cells (commonly called “C-cells”), via amino acid transporters. Amino acid transporters up-regulate in many cancers, and their expression level associate with clinical aggressiveness and prognosis. This is the review to discuss the therapeutic potential of amino acid transporters and as molecular targets in thyroid cancer.

Keyword

Thyroid neoplasms; Large neutral amino acid-transporter 1; Amino acid transport systems; 2-amino-3-(4-((5-amino-2-phenylbenzo(d)oxazol-7-yl)methoxy)-3,5-dichlorophenyl)propanoic acid; Boron neutron capture therapy; Proto-oncogene proteins c-myc

Figure

• 

  Fig. 1 Schematic representation of the nuclear capture reaction in Boron neutron capture therapy. On irradiation of the 10B compound, p-boronophenylalanine (BPA), with thermal neutrons, alpha particles and lithium nuclei are obtained, subsequently damaging cancer cells selectively. The track ranges of the two emitted particles within the body are approximately 5 to 9 μm, and this distance is not greater than the diameter of the cancer cells. The emitted particles thus damage only the cancer cell nuclei and do not approach adjacent normal cells. Therefore, damage is suppressed in normal cells, since they do not take up BPA via L-type amino acid transporter 1 (LAT1), and cancer cells are selectively damaged.

Reference

1. Zhu J, Thompson CB. Metabolic regulation of cell growth and proliferation. Nat Rev Mol Cell Biol. 2019; 20:436–50.

2. Martinez-Outschoorn UE, Peiris-Pages M, Pestell RG, Sotgia F, Lisanti MP. Cancer metabolism: a therapeutic perspective. Nat Rev Clin Oncol. 2017; 14:11–31.

3. He Y, Gao M, Tang H, Cao Y, Liu S, Tao Y. Metabolic intermediates in tumorigenesis and progression. Int J Biol Sci. 2019; 15:1187–99.

4. Vettore L, Westbrook RL, Tennant DA. New aspects of amino acid metabolism in cancer. Br J Cancer. 2020; 122:150–6.

5. Tortolero-Luna G, Torres-Cintron CR, Alvarado-Ortiz M, Ortiz-Ortiz KJ, Zavala-Zegarra DE, Mora-Pinero E. Incidence of thyroid cancer in Puerto Rico and the US by racial/ethnic group, 2011–2015. BMC Cancer. 2019; 19:637.

6. Ahn HS, Kim HJ, Kim KH, Lee YS, Han SJ, Kim Y, et al. Thyroid cancer screening in South Korea increases detection of papillary cancers with no impact on other subtypes or thyroid cancer mortality. Thyroid. 2016; 26:1535–40.

7. Iniguez-Ariza NM, Brito JP. Management of low-risk papillary thyroid cancer. Endocrinol Metab (Seoul). 2018; 33:185–94.

8. Ito Y, Uruno T, Nakano K, Takamura Y, Miya A, Kobayashi K, et al. An observation trial without surgical treatment in patients with papillary microcarcinoma of the thyroid. Thyroid. 2003; 13:381–7.

9. Ito Y, Miyauchi A, Inoue H, Fukushima M, Kihara M, Higashiyama T, et al. An observational trial for papillary thyroid microcarcinoma in Japanese patients. World J Surg. 2010; 34:28–35.

10. Sugitani I, Toda K, Yamada K, Yamamoto N, Ikenaga M, Fujimoto Y. Three distinctly different kinds of papillary thyroid microcarcinoma should be recognized: our treatment strategies and outcomes. World J Surg. 2010; 34:1222–31.

11. Salehian B, Liem SY, Mojazi Amiri H, Maghami E. Clinical trials in management of anaplastic thyroid carcinoma; progressions and set backs: a systematic review. Int J Endocrinol Metab. 2019; 17:e67759.

12. Sugitani I, Miyauchi A, Sugino K, Okamoto T, Yoshida A, Suzuki S. Prognostic factors and treatment outcomes for anaplastic thyroid carcinoma: ATC Research Consortium of Japan cohort study of 677 patients. World J Surg. 2012; 36:1247–54.

13. Hediger MA, Clemencon B, Burrier RE, Bruford EA. The ABCs of membrane transporters in health and disease (SLC series): introduction. Mol Aspects Med. 2013; 34:95–107.

14. Kanai Y, Segawa H, Miyamoto Ki, Uchino H, Takeda E, Endou H. Expression cloning and characterization of a transporter for large neutral amino acids activated by the heavy chain of 4F2 antigen (CD98). J Biol Chem. 1998; 273:23629–32.

15. Mastroberardino L, Spindler B, Pfeiffer R, Skelly PJ, Loffing J, Shoemaker CB, et al. Amino-acid transport by heterodimers of 4F2hc/CD98 and members of a permease family. Nature. 1998; 395:288–91.

16. Rossier G, Meier C, Bauch C, Summa V, Sordat B, Verrey F, et al. LAT2, a new basolateral 4F2hc/CD98-associated amino acid transporter of kidney and intestine. J Biol Chem. 1999; 274:34948–54.

17. Segawa H, Fukasawa Y, Miyamoto K, Takeda E, Endou H, Kanai Y. Identification and functional characterization of a Na+-independent neutral amino acid transporter with broad substrate selectivity. J Biol Chem. 1999; 274:19745–51.

18. Pineda M, Fernandez E, Torrents D, Estevez R, Lopez C, Camps M, et al. Identification of a membrane protein, LAT-2, that co-expresses with 4F2 heavy chain, an L-type amino acid transport activity with broad specificity for small and large zwitterionic amino acids. J Biol Chem. 1999; 274:19738–44.

19. Nakada N, Mikami T, Hana K, Ichinoe M, Yanagisawa N, Yoshida T, et al. Unique and selective expression of L-amino acid transporter 1 in human tissue as well as being an aspect of oncofetal protein. Histol Histopathol. 2014; 29:217–27.

20. Hafliger P, Charles RP. The L-type amino acid transporter LAT1: an emerging target in cancer. Int J Mol Sci. 2019; 20:2428.

21. Cormerais Y, Giuliano S, LeFloch R, Front B, Durivault J, Tambutte E, et al. Genetic disruption of the multifunctional CD98/LAT1 complex demonstrates the key role of essential amino acid transport in the control of mTORC1 and tumor growth. Cancer Res. 2016; 76:4481–92.

22. Furuya M, Horiguchi J, Nakajima H, Kanai Y, Oyama T. Correlation of L-type amino acid transporter 1 and CD98 expression with triple negative breast cancer prognosis. Cancer Sci. 2012; 103:382–9.

23. Shi L, Luo W, Huang W, Huang S, Huang G. Downregulation of L-type amino acid transporter 1 expression inhibits the growth, migration and invasion of gastric cancer cells. Oncol Lett. 2013; 6:106–12.

24. Hafliger P, Graff J, Rubin M, Stooss A, Dettmer MS, Altmann KH, et al. The LAT1 inhibitor JPH203 reduces growth of thyroid carcinoma in a fully immunocompetent mouse model. J Exp Clin Cancer Res. 2018; 37:234.

25. Shen L, Qian C, Cao H, Wang Z, Luo T, Liang C. Upregulation of the solute carrier family 7 genes is indicative of poor prognosis in papillary thyroid carcinoma. World J Surg Oncol. 2018; 16:235.

26. Enomoto K, Sato F, Tamagawa S, Gunduz M, Onoda N, Uchino S, et al. A novel therapeutic approach for anaplastic thyroid cancer through inhibition of LAT1. Sci Rep. 2019; 9:14616.

27. Barollo S, Bertazza L, Watutantrige-Fernando S, Censi S, Cavedon E, Galuppini F, et al. Overexpression of L-type amino acid transporter 1 (LAT1) and 2 (LAT2): novel markers of neuroendocrine tumors. PLoS One. 2016; 11:e0156044.

28. Braun D, Wirth EK, Wohlgemuth F, Reix N, Klein MO, Gruters A, et al. Aminoaciduria, but normal thyroid hormone levels and signalling, in mice lacking the amino acid and thyroid hormone transporter Slc7a8. Biochem J. 2011; 439:249–55.

29. Verrey F, Closs EI, Wagner CA, Palacin M, Endou H, Kanai Y. CATs and HATs: the SLC7 family of amino acid transporters. Pflugers Arch. 2004; 447:532–42.

30. Badziong J, Ting S, Synoracki S, Tiedje V, Brix K, Brabant G, et al. Differential regulation of monocarboxylate transporter 8 expression in thyroid cancer and hyperthyroidism. Eur J Endocrinol. 2017; 177:243–50.

31. Babu E, Kanai Y, Chairoungdua A, Kim DK, Iribe Y, Tangtrongsup S, et al. Identification of a novel system L amino acid transporter structurally distinct from heterodimeric amino acid transporters. J Biol Chem. 2003; 278:43838–45.

32. Cole KA, Chuaqui RF, Katz K, Pack S, Zhuang Z, Cole CE, et al. cDNA sequencing and analysis of POV1 (PB39): a novel gene up-regulated in prostate cancer. Genomics. 1998; 51:282–7.

33. Wang Q, Bailey CG, Ng C, Tiffen J, Thoeng A, Minhas V, et al. Androgen receptor and nutrient signaling pathways coordinate the demand for increased amino acid transport during prostate cancer progression. Cancer Res. 2011; 71:7525–36.

34. Bodoy S, Martin L, Zorzano A, Palacin M, Estevez R, Bertran J. Identification of LAT4, a novel amino acid transporter with system L activity. J Biol Chem. 2005; 280:12002–11.

35. Fuchs BC, Finger RE, Onan MC, Bode BP. ASCT2 silencing regulates mammalian target-of-rapamycin growth and survival signaling in human hepatoma cells. Am J Physiol Cell Physiol. 2007; 293:C55–63.

36. Kanai Y, Hediger MA. The glutamate and neutral amino acid transporter family: physiological and pharmacological implications. Eur J Pharmacol. 2003; 479:237–47.

37. Zhang Z, Liu R, Shuai Y, Huang Y, Jin R, Wang X, et al. ASCT2 (SLC1A5)-dependent glutamine uptake is involved in the progression of head and neck squamous cell carcinoma. Br J Cancer. 2020; 122:82–93.

38. Liu Y, Zhao T, Li Z, Wang L, Yuan S, Sun L. The role of ASCT2 in cancer: a review. Eur J Pharmacol. 2018; 837:81–7.

39. Kim HM, Lee YK, Koo JS. Expression of glutamine metabolism-related proteins in thyroid cancer. Oncotarget. 2016; 7:53628–41.

40. Pramod AB, Foster J, Carvelli L, Henry LK. SLC6 transporters: structure, function, regulation, disease association and therapeutics. Mol Aspects Med. 2013; 34:197–219.

41. Coothankandaswamy V, Cao S, Xu Y, Prasad PD, Singh PK, Reynolds CP, et al. Amino acid transporter SLC6A14 is a novel and effective drug target for pancreatic cancer. Br J Pharmacol. 2016; 173:3292–306.

42. Polewski MD, Reveron-Thornton RF, Cherryholmes GA, Marinov GK, Aboody KS. SLC7A11 overexpression in glioblastoma is associated with increased cancer stem cell-like properties. Stem Cells Dev. 2017; 26:1236–46.

43. Takeuchi S, Wada K, Toyooka T, Shinomiya N, Shimazaki H, Nakanishi K, et al. Increased xCT expression correlates with tumor invasion and outcome in patients with glioblastomas. Neurosurgery. 2013; 72:33–41.

44. Vekony N, Wolf S, Boissel JP, Gnauert K, Closs EI. Human cationic amino acid transporter hCAT-3 is preferentially expressed in peripheral tissues. Biochemistry. 2001; 40:12387–94.

45. El Ansari R, Craze ML, Miligy I, Diez-Rodriguez M, Nolan CC, Ellis IO, et al. The amino acid transporter SLC7A5 confers a poor prognosis in the highly proliferative breast cancer subtypes and is a key therapeutic target in luminal B tumours. Breast Cancer Res. 2018; 20:21.

46. Bik-Multanowski M, Pietrzyk JJ. LAT1 gene variants: potential factors influencing the clinical course of phenylketonuria. J Inherit Metab Dis. 2006; 29:684.

47. Espino Guarch M, Font-Llitjos M, Murillo-Cuesta S, Errasti-Murugarren E, Celaya AM, Girotto G, et al. Mutations in L-type amino acid transporter-2 support SLC7A8 as a novel gene involved in age-related hearing loss. Elife. 2018; 7:e31511.

48. Ito T, Seyama T, Hayashi Y, Hayashi T, Dohi K, Mizuno T, et al. Establishment of 2 human thyroid-carcinoma cell-lines (8305c, 8505c) bearing p53 gene-mutations. Int J Oncol. 1994; 4:583–6.

49. Zhang L, Zhang Y, Mehta A, Boufraqech M, Davis S, Wang J, et al. Dual inhibition of HDAC and EGFR signaling with CUDC-101 induces potent suppression of tumor growth and metastasis in anaplastic thyroid cancer. Oncotarget. 2015; 6:9073–85.

50. Kaira K, Oriuchi N, Imai H, Shimizu K, Yanagitani N, Sunaga N, et al. Prognostic significance of L-type amino acid transporter 1 expression in resectable stage I–III nonsmall cell lung cancer. Br J Cancer. 2008; 98:742–8.

51. Ichinoe M, Yanagisawa N, Mikami T, Hana K, Nakada N, Endou H, et al. L-type amino acid transporter 1 (LAT1) expression in lymph node metastasis of gastric carcinoma: its correlation with size of metastatic lesion and Ki-67 labeling. Pathol Res Pract. 2015; 211:533–8.

52. Kaira K, Oriuchi N, Imai H, Shimizu K, Yanagitani N, Sunaga N, et al. Expression of L-type amino acid transporter 1 (LAT1) in neuroendocrine tumors of the lung. Pathol Res Pract. 2008; 204:553–61.

53. Janpipatkul K, Suksen K, Borwornpinyo S, Jearawiriyapaisarn N, Hongeng S, Piyachaturawat P, et al. Downregulation of LAT1 expression suppresses cholangiocarcinoma cell invasion and migration. Cell Signal. 2014; 26:1668–79.

54. Kaji M, Kabir-Salmani M, Anzai N, Jin CJ, Akimoto Y, Horita A, et al. Properties of L-type amino acid transporter 1 in epidermal ovarian cancer. Int J Gynecol Cancer. 2010; 20:329–36.

55. McClellan WM, Schafer JA. Transport of the amino acid analog, 2-aminobicyclo(2,2,1)-heptane-2-carboxylic acid, by Ehrlich ascites tumor cells. Biochim Biophys Acta. 1973; 311:462–75.

56. Kim CS, Cho SH, Chun HS, Lee SY, Endou H, Kanai Y, et al. BCH, an inhibitor of system L amino acid transporters, induces apoptosis in cancer cells. Biol Pharm Bull. 2008; 31:1096–100.

57. Oda K, Hosoda N, Endo H, Saito K, Tsujihara K, Yamamura M, et al. L-type amino acid transporter 1 inhibitors inhibit tumor cell growth. Cancer Sci. 2010; 101:173–9.

58. Kongpracha P, Nagamori S, Wiriyasermkul P, Tanaka Y, Kaneda K, Okuda S, et al. Structure-activity relationship of a novel series of inhibitors for cancer type transporter L-type amino acid transporter 1 (LAT1). J Pharmacol Sci. 2017; 133:96–102.

59. Okano N, Naruge D, Kawai K, Kobayashi T, Nagashima F, Endou H, et al. First-in-human phase I study of JPH203, an L-type amino acid transporter 1 inhibitor, in patients with advanced solid tumors. Invest New Drugs. 2020; Mar. 20. [Epub]. https://doi.org/10.1007/s10637-020-00924-3.

60. Al Moudi M, Sun Z, Lenzo N. Diagnostic value of SPECT, PET and PET/CT in the diagnosis of coronary artery disease: a systematic review. Biomed Imaging Interv J. 2011; 7:e9.

61. Gatenby RA, Gillies RJ. Why do cancers have high aerobic glycolysis? Nat Rev Cancer. 2004; 4:891–9.

62. Khan N, Oriuchi N, Higuchi T, Zhang H, Endo K. PET in the follow-up of differentiated thyroid cancer. Br J Radiol. 2003; 76:690–5.

63. Kim H, Na KJ, Choi JH, Ahn BC, Ahn D, Sohn JH. Feasibility of FDG-PET/CT for the initial diagnosis of papillary thyroid cancer. Eur Arch Otorhinolaryngol. 2016; 273:1569–76.

64. Feine U, Lietzenmayer R, Hanke JP, Wohrle H, Muller-Schauenburg W. 18FDG whole-body PET in differentiated thyroid carcinoma: flipflop in uptake patterns of 18FDG and 131I. Nuklearmedizin. 1995; 34:127–34.

65. Feine U, Lietzenmayer R, Hanke JP, Held J, Wohrle H, Muller-Schauenburg W. Fluorine-18-FDG and iodine-131-iodide uptake in thyroid cancer. J Nucl Med. 1996; 37:1468–72.

66. Chen W, Parsons M, Torigian DA, Zhuang H, Alavi A. Evaluation of thyroid FDG uptake incidentally identified on FDG-PET/CT imaging. Nucl Med Commun. 2009; 30:240–4.

67. Katayama D, Watabe T, Nagamori S, Kanai Y, Naka S, Liu Y, et al. Preclinical evaluation of new PET tracer targeting L-type amino acid transporter 1 (LAT1): F-18 NKO-035 PET in inflammation model of rats. J Nucl Med. 2018; 59(Suppl 1):1121.

68. Beheshti M, Pocher S, Vali R, Waldenberger P, Broinger G, Nader M, et al. The value of 18F-DOPA PET-CT in patients with medullary thyroid carcinoma: comparison with 18F-FDG PET-CT. Eur Radiol. 2009; 19:1425–34.

69. Giovanella L, Treglia G, Iakovou I, Mihailovic J, Verburg FA, Luster M. EANM practice guideline for PET/CT imaging in medullary thyroid carcinoma. Eur J Nucl Med Mol Imaging. 2020; 47:61–77.

70. Phan HT, Jager PL, Plukker JT, Wolffenbuttel BH, Dierckx RA, Links TP. Comparison of 11C-methionine PET and 18F-fluorodeoxyglucose PET in differentiated thyroid cancer. Nucl Med Commun. 2008; 29:711–6.

71. Barth RF, Coderre JA, Vicente MG, Blue TE. Boron neutron capture therapy of cancer: current status and future prospects. Clin Cancer Res. 2005; 11:3987–4002.

72. Das BC, Thapa P, Karki R, Schinke C, Das S, Kambhampati S, et al. Boron chemicals in diagnosis and therapeutics. Future Med Chem. 2013; 5:653–76.

73. Detta A, Cruickshank GS. L-amino acid transporter-1 and boronophenylalanine-based boron neutron capture therapy of human brain tumors. Cancer Res. 2009; 69:2126–32.

74. Wongthai P, Hagiwara K, Miyoshi Y, Wiriyasermkul P, Wei L, Ohgaki R, et al. Boronophenylalanine, a boron delivery agent for boron neutron capture therapy, is transported by ATB0,+, LAT1 and LAT2. Cancer Sci. 2015; 106:279–86.

75. Watabe T, Ikeda H, Nagamori S, Wiriyasermkul P, Tanaka Y, Naka S, et al. 18F-FBPA as a tumor-specific probe of L-type amino acid transporter 1 (LAT1): a comparison study with 18F-FDG and 11C-Methionine PET. Eur J Nucl Med Mol Imaging. 2017; 44:321–31.

76. Sauerwein W, Wittig A, Moss R, Nakagawa Y. Neutron capture therapy. Berlin: Springer;2012. Chapter 4:Compact Neutron Generator for BNCT. p. 55–68.

77. Dagrosa MA, Viaggi M, Kreimann E, Farias S, Garavaglia R, Agote M, et al. Selective uptake of p-borophenylalanine by undifferentiated thyroid carcinoma for boron neutron capture therapy. Thyroid. 2002; 12:7–12.

78. Dagrosa MA, Viaggi M, Longhino J, Calzetta O, Cabrini R, Edreira M, et al. Experimental application of boron neutron capture therapy to undifferentiated thyroid carcinoma. Int J Radiat Oncol Biol Phys. 2003; 57:1084–92.

79. Dagrosa MA, Thomasz L, Longhino J, Perona M, Calzetta O, Blaumann H, et al. Optimization of boron neutron capture therapy for the treatment of undifferentiated thyroid cancer. Int J Radiat Oncol Biol Phys. 2007; 69:1059–66.

80. Hayashi K, Jutabha P, Endou H, Anzai N. c-Myc is crucial for the expression of LAT1 in MIA Paca-2 human pancreatic cancer cells. Oncol Rep. 2012; 28:862–6.

81. Wierstra I, Alves J. The c-myc promoter: still MysterY and challenge. Adv Cancer Res. 2008; 99:113–333.

82. Vita M, Henriksson M. The Myc oncoprotein as a therapeutic target for human cancer. Semin Cancer Biol. 2006; 16:318–30.

83. Bieche I, Franc B, Vidaud D, Vidaud M, Lidereau R. Analyses of MYC, ERBB2, and CCND1 genes in benign and malignant thyroid follicular cell tumors by real-time polymerase chain reaction. Thyroid. 2001; 11:147–52.

84. Sakr HI, Chute DJ, Nasr C, Sturgis CD. cMYC expression in thyroid follicular cell-derived carcinomas: a role in thyroid tumorigenesis. Diagn Pathol. 2017; 12:71.

85. Zhu X, Enomoto K, Zhao L, Zhu YJ, Willingham MC, Meltzer P, et al. Bromodomain and extraterminal protein inhibitor JQ1 suppresses thyroid tumor growth in a mouse model. Clin Cancer Res. 2017; 23:430–40.

86. Enomoto K, Zhu X, Park S, Zhao L, Zhu YJ, Willingham MC, et al. Targeting MYC as a therapeutic intervention for anaplastic thyroid cancer. J Clin Endocrinol Metab. 2017; 102:2268–80.

87. Elorza A, Soro-Arnaiz I, Melendez-Rodriguez F, Rodriguez-Vaello V, Marsboom G, de Carcer G, et al. HIF2α acts as an mTORC1 activator through the amino acid carrier SLC7A5. Mol Cell. 2012; 48:681–91.

88. Onishi Y, Hiraiwa M, Kamada H, Iezaki T, Yamada T, Kaneda K, et al. Hypoxia affects Slc7a5 expression through HIF-2α in differentiated neuronal cells. FEBS Open Bio. 2019; 9:241–7.

89. Tomblin JK, Arthur S, Primerano DA, Chaudhry AR, Fan J, Denvir J, et al. Aryl hydrocarbon receptor (AHR) regulation of L-type amino acid transporter 1 (LAT-1) expression in MCF-7 and MDA-MB-231 breast cancer cells. Biochem Pharmacol. 2016; 106:94–103.

90. Grzes KM, Swamy M, Hukelmann JL, Emslie E, Sinclair LV, Cantrell DA. Control of amino acid transport coordinates metabolic reprogramming in T-cell malignancy. Leukemia. 2017; 31:2771–9.

91. Dann SG, Ryskin M, Barsotti AM, Golas J, Shi C, Miranda M, et al. Reciprocal regulation of amino acid import and epigenetic state through Lat1 and EZH2. EMBO J. 2015; 34:1773–85.