Open Access

Perspectives of small molecule inhibitors of activin receptor‑like kinase in anti‑tumor treatment and stem cell differentiation (Review)

  • Authors:
    • Xueling Cui
    • Shumi Shang
    • Xinran Lv
    • Jing Zhao
    • Yan Qi
    • Zhonghui Liu
  • View Affiliations

  • Published online on: April 30, 2019     https://doi.org/10.3892/mmr.2019.10209
  • Pages: 5053-5062
  • Copyright: © Cui et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Activin receptor‑like kinases (ALKs), members of the type I activin receptor family, belong to the serine/threonine kinase receptors of the transforming growth factor‑β (TGF‑β) superfamily. ALKs mediate the roles of activin/TGF‑β in a wide variety of physiological and pathological processes, ranging from cell differentiation and proliferation to apoptosis. For example, the activities of ALKs are associated with an advanced tumor stage in prostate cancer and the chondrogenic differentiation of mesenchymal stem cells. Therefore, potent and selective small molecule inhibitors of ALKs would not only aid in investigating the function of activin/TGF‑β, but also in developing treatments for these diseases via the disruption of activin/TGF‑β. In recent studies, several ALK inhibitors, including LY‑2157299, SB‑431542 and A‑83‑01, have been identified and have been confirmed to affect stem cell differentiation and tumor progression in animal models. This review discusses the therapeutic perspective of small molecule inhibitors of ALKs as drug targets in tumor and stem cells.

References

1 

Mathews LS and Vale WW: Expression cloning of an activin receptor, a predicted transmembrane serine kinase. Cell. 65:973–982. 1991. View Article : Google Scholar : PubMed/NCBI

2 

Mathews LS, Vale WW and Kintner CR: Cloning of a second type of activin receptor and functional characterization in Xenopus embryos. Science. 255:1702–1705. 1992. View Article : Google Scholar : PubMed/NCBI

3 

Attisano L, Wrana JL, Cheifetz S and Massagué J: Novel activin receptors: Distinct genes and alternative mRNA splicing generate a repertoire of serine/threonine kinase receptors. Cell. 68:97–108. 1992. View Article : Google Scholar : PubMed/NCBI

4 

Tsuchida K, Mathews LS and Vale WW: Cloning and characterization of a transmembrane serine kinase that acts as an activin type I receptor. Proc Natl Acad Sci USA. 90:11242–11246. 1993. View Article : Google Scholar : PubMed/NCBI

5 

Hu-Lowe DD, Chen E, Zhang L, Watson KD, Mancuso P, Lappin P, Wickman G, Chen JH, Wang J, Jiang X, et al: Targeting activin receptor-like kinase 1 inhibits angiogenesis and tumorigenesis through a mechanism of action complementary to anti-VEGF therapies. Cancer Res. 71:1362–1373. 2011. View Article : Google Scholar : PubMed/NCBI

6 

Johnson DW, Berg JN, Baldwin MA, Gallione CJ, Marondel I, Yoon SJ, Stenzel TT, Speer M, Pericak-Vance MA, Diamond A, et al: Mutations in the activin receptor-like kinase 1 gene in hereditary haemorrhagic telangiectasia type 2. Nat Genet. 13:189–195. 1996. View Article : Google Scholar : PubMed/NCBI

7 

Muñoz-Félix JM, López-Novoa JM and Martínez-Salgado C: Heterozygous disruption of activin receptor-like kinase 1 is associated with increased renal fibrosis in a mouse model of obstructive nephropathy. Kidney Int. 85:319–332. 2014. View Article : Google Scholar : PubMed/NCBI

8 

Song T, Zhao J, Jiang T, Jin X, Li Y and Liu X: Formononetin protects against balloon injury-induced neointima formation in rats by regulating proliferation and migration of vascular smooth muscle cells via the TGF β1/Smad3 signaling pathway. Int J Mol Med. 42:2155–2162. 2018.PubMed/NCBI

9 

Liu H, Zhong L, Yuan T, Chen S, Zhou Y, An L, Guo Y, Fan M, Li Y, Sun Y, et al: MicroRNA-155 inhibits the osteogenic differentiation of mesenchymal stem cells induced by BMP9 via downregulation of BMP signaling pathway. Int J Mol Med. 41:3379–3393. 2018.PubMed/NCBI

10 

Takahashi S, Nakasatomi M, Takei Y, Ikeuchi H, Sakairi T, Kaneko Y, Hiromura K, Nojima Y and Maeshima A: Identification of urinary activin A as a novel biomarker reflecting the severity of acute kidney injury. Sci Rep. 8:51762018. View Article : Google Scholar : PubMed/NCBI

11 

Pirruccello-Straub M, Jackson J, Wawersik S, Webster MT, Salta L, Long K, McConaughy W, Capili A, Boston C, Carven GJ, et al: Blocking extracellular activation of myostatin as a strategy for treating muscle wasting. Sci Rep. 8:22922018. View Article : Google Scholar : PubMed/NCBI

12 

Donovan P, Dubey OA, Kallioinen S, Rogers KW, Muehlethaler K, Müller P, Rimoldi D and Constam DB: Paracrine activin-A signaling promotes melanoma growth and metastasis through immune evasion. J Invest Dermatol. 137:2578–2587. 2017. View Article : Google Scholar : PubMed/NCBI

13 

Wang Q, Yu Y, Zhang P, Chen Y, Li C, Chen J, Wang Y and Li Y: The crucial role of activin A/ALK4 pathway in the pathogenesis of Ang-II-induced atrial fibrosis and vulnerability to atrial fibrillation. Basic Res Cardiol. 112:472017. View Article : Google Scholar : PubMed/NCBI

14 

Xie D, Liu Z, Wu J, Feng W, Yang K, Deng J, Tian G, Santos S, Cui X and Lin F: The effects of activin A on the migration of human breast cancer cells and neutrophils and their migratory interaction. Exp Cell Res. 357:107–115. 2017. View Article : Google Scholar : PubMed/NCBI

15 

Heldin CH, Miyazono K and Ten Dijke P: TGF-beta signaling from cell membrane to nucleus through SMAD proteins. Nature. 390:465–471. 1997. View Article : Google Scholar : PubMed/NCBI

16 

Massagué J and Gomis RR: The logic of TGFbeta signaling. FEBS Lett. 580:2811–2820. 2006. View Article : Google Scholar : PubMed/NCBI

17 

Hawinkels LJ, Garcia de Vinuesa A and Ten Dijke P: Activin receptor-like kinase 1 as a target for anti-angiogenesis therapy. Expert Opin Investig Drugs. 22:1371–1383. 2013. View Article : Google Scholar : PubMed/NCBI

18 

Hinck AP, Mueller TD and Springer TA: Structural biology and evolution of the TGF-β family. Cold Spring Harb Perspect Biol. 8(pii): a0221032016. View Article : Google Scholar : PubMed/NCBI

19 

Niu L, Cui X, Qi Y, Xie D, Wu Q, Chen X, Ge J and Liu Z: Involvement of TGF-β1/Smad3 signaling in carbon tetrachloride-induced acute liver injury in mice. PLoS One. 11:e01560902016. View Article : Google Scholar : PubMed/NCBI

20 

Afrakhte M, Morén A, Jossan S, Itoh S, Sampath K, Westermark B, Heldin CH, Heldin NE and Ten Dijke P: Induction of inhibitory Smad6 and Smad7 mRNA by TGF-beta family members. Biochem Biophys Res Commun. 249:505–511. 1998. View Article : Google Scholar : PubMed/NCBI

21 

Qi Y, Ge J, Ma C, Wu N, Cui X and Liu Z: Activin A regulates activation of mouse neutrophils by Smad3 signalling. Open Biol. 7(pii): 1603422017. View Article : Google Scholar : PubMed/NCBI

22 

Moustakas A and Heldin CH: Non-Smad TGF-beta signals. J Cell Sci. 118:3573–3584. 2005. View Article : Google Scholar : PubMed/NCBI

23 

Zhang YE: Non-Smad pathways in TGF-beta signaling. Cell Res. 19:128–139. 2009. View Article : Google Scholar : PubMed/NCBI

24 

Kua HY, Liu H, Leong WF, Li L, Jia D, Ma G, Hu Y, Wang X, Chau JF, Chen YG, et al: c-Abl promotes osteoblast expansion by differentially regulating canonical and non-canonical BMP pathways and p16INK4a expression. Nat Cell Biol. 14:727–737. 2012. View Article : Google Scholar : PubMed/NCBI

25 

Li Z, Fei T, Zhang J, Zhu G, Wang L, Lu D, Chi X, Teng Y, Hou N, Yang X, et al: BMP4 signaling acts via dual-specificity phosphatase 9 to control ERK activity in mouse embryonic stem cells. Cell Stem Cell. 10:171–182. 2012. View Article : Google Scholar : PubMed/NCBI

26 

Suzuki K, Kobayashi T, Funatsu O, Morita A and Ikekita M: Activin A induces neuronal differentiation and survival via ALK4 in a SMAD-independent manner in a subpopulation of human neuroblastomas. Biochem Biophys Res Commun. 394:639–645. 2010. View Article : Google Scholar : PubMed/NCBI

27 

Shoji H, Tsuchida K, Kishi H, Yamakawa N, Matsuzaki T, Liu Z, Nakamura T and Sugino H: Identification and characterization of a PDZ protein that interacts with activin types II receptors. J Bol Chem. 275:5485–5492. 2000. View Article : Google Scholar

28 

Kurisaki A, Inoue I, Kurisaki K, Yamakawa N, Tsuchida K and Sugino H: Activin induces long-lasting N-methyl-D-aspartate receptor activation via scaffolding PDZ protein activin receptor interacting protein 1. Neuroscience. 151:1225–1235. 2008. View Article : Google Scholar : PubMed/NCBI

29 

Fanning AS and Anderson JM: PDZ domains: Fundamental building blocks in the organization of protein complexes at the plasma membrane. J Clin Invest. 103:767–772. 1999. View Article : Google Scholar : PubMed/NCBI

30 

Tsuchida K, Matsuzaki T, Yamakawa N, Liu ZH and Sugino H: Intracellular and extracellular control of activin function by novel regulatory molecules. Mol Cell Endocrinol. 180:25–31. 2001. View Article : Google Scholar : PubMed/NCBI

31 

Matsuzaki T, Hanai S, Kishi H, Liu Z, Bao Y, Kikuchi A, Tsuchida K and Sugino H: Regulation of endocytosisi of activin type II receptors by a novel PDZ protein through Ral/Ral-binding protein 1-dependent pathway. J Biol Chem. 277:19008–19018. 2002. View Article : Google Scholar : PubMed/NCBI

32 

Liu ZH, Tsuchida K, Matsuzaki T, Bao YL, Kurisaki A and Sugino H: Characterization of isoforms of activin receptor-interacting protein 2 that augment activin signaling. J Endocrinol. 189:409–421. 2006. View Article : Google Scholar : PubMed/NCBI

33 

Liu HY, Chen FF, Ge JY, Wang YN, Zhang CH, Cui XL, Yu F Tai GX and Liu ZH: Expression and localization of activin receptor-interacting protein 2 in mouse tissues. Gen Comp Endocrinol. 161:276–282. 2009. View Article : Google Scholar : PubMed/NCBI

34 

Qi Y, Ge JY, Wang YN, Liu HY, Li YM, Liu ZH and Cui XL: Co-expression of activin receptor-interacting protein 1 and 2 in mouse nerve cells. Neurosci Lett. 542:53–58. 2013. View Article : Google Scholar : PubMed/NCBI

35 

Liu HY, Wang YN, Ge JY, Li N, Cui XL and Liu ZH: Localization and role of activin receptor-interacting protein 1 in mouse brain. J Neuroendocrinol. 25:87–95. 2013. View Article : Google Scholar : PubMed/NCBI

36 

Manavski Y, Abel T, Hu J, Kleinlützum D, Buchholz CJ, Belz C, Augustin HG, Boon RA and Dimmeler S: Endothelial transcription factor KLF2 negatively regulates liver regeneration via induction of activin A. Proc Natl Acad Sci USA. 114:3993–3998. 2017. View Article : Google Scholar : PubMed/NCBI

37 

Wei Q, Wang YN, Liu HY, Yang J, Yang CY, Liu M, Liu YF, Yang P and Liu ZH: The expression and role of activin A and follistatin in heart failure rats after myocardial infarction. Int J Cardiol. 168:2994–2997. 2013. View Article : Google Scholar : PubMed/NCBI

38 

Ogawa K, Funaba M, Chen Y and Tsujimoto M: Activin A functions as a Th2 cytokine in the promotion of the alternative activation of macrophages. J Immunol. 177:6787–6794. 2006. View Article : Google Scholar : PubMed/NCBI

39 

Li N, Cui X, Ge J, Li J, Niu L, Liu H, Qi Y, Liu Z and Wang Y: Activin A inhibits activities of lipopolysaccharide-activated macrophages via TLR4, not of TLR2. Biochem Biophys Res Commun. 435:222–228. 2013. View Article : Google Scholar : PubMed/NCBI

40 

Schubert D, Kimura H, LaCorbiere M, Vaughan J, Karr D and Fische WH: Activin is a nerve cell survival molecule. Nature. 344:868–870. 1990. View Article : Google Scholar : PubMed/NCBI

41 

Fang L, Wang YN, Cui XL, Fang SY, Ge JY, Sun Y and Liu ZH: The role and mechanism of action of activin A in neurite outgrowth of chicken embryonic dorsal root ganglia. J Cell Sci. 125:1500–1507. 2012. View Article : Google Scholar : PubMed/NCBI

42 

Ottley EC, Nicholson HD and Gold EJ: Activin A regulates microRNAs and gene expression in LNCaP cells. Prostate. 76:951–963. 2016. View Article : Google Scholar : PubMed/NCBI

43 

Loomans HA and Andl CD: Intertwining of activin A and TGFβ signaling: Dual roles in cancer progression and cancer cell invasion. Cancers (Basel). 7:70–91. 2014. View Article : Google Scholar : PubMed/NCBI

44 

Wu S, Qi Y, Niu LM, Xie DX, Cui XL and Liu ZH: Activin A as a novel biomarker for colorectal adenocarcinoma in humans. Eur Rev Med Pharmacol Sci. 19:4371–4378. 2015.PubMed/NCBI

45 

Steller MD, Shaw TJ, Vanderhyden BC and Ethier JF: Inhibin resistance is associated with aggressive tumorigenicity of ovarian cancer cells. Mol Cancer Res. 3:50–61. 2005.PubMed/NCBI

46 

Bashir M, Damineni S, Mukherjee G and Kondaiah P: Activin-A signaling promotes epithelial-mesenchymal transition, invasion, and metastatic growth of breast cancer. NPJ Breast Cancer. 1:150072015. View Article : Google Scholar : PubMed/NCBI

47 

Kalli M, Mpekris F, Wong CK, Panagi M, Ozturk S, Thiagalingam S, Stylianopoulos T and Papageorgis P: Activin A signaling regulates IL13Rα2 expression to promote breast cancer metastasis. Front Oncol. 9:322019. View Article : Google Scholar : PubMed/NCBI

48 

Chang KP, Kao HK, Liang Y, Cheng MH, Chang YL, Liu SC, Lin YC, Ko TY, Lee YS, Tsai CL, et al: Overexpression of activin a in oral squamous cell carcinoma: Association with poor prognosis and tumor progression. Ann Surg Oncol. 17:1945–1956. 2010. View Article : Google Scholar : PubMed/NCBI

49 

Chen JL, Walton KL, Qian H, Colgan TD, Hagg A, WattM J, Harrison CA and Gregorevic P: Differential effects of Il6 and activin a in the development of cancer-associated cachexia. Cancer Res. 76:5372–5382. 2016. View Article : Google Scholar : PubMed/NCBI

50 

Loumaye A, de Barsy M, Nachit M, Lause P, van Maanen A, Trefois P, Gruson D and Thissen JP: Circulating Activin A predicts survival in cancer patients. J Cachexia Sarcopenia Muscle. 8:768–777. 2017. View Article : Google Scholar : PubMed/NCBI

51 

Loumaye A, de Barsy M, Nachit M, Lause P, Frateur L, van Maanen A, Trefois P, Gruson D and Thissen JP: Role of activin a and myostatin in human cancer cachexia. J Clin Endocrinol Metab. 100:2030–2038. 2015. View Article : Google Scholar : PubMed/NCBI

52 

Burdette JE, Jeruss JS, Kurley SJ, Lee EJ and Woodruff TK: Activin A mediates growth inhibition and cell cycle arrest through Smads in human breast cancer cells. Cancer Res. 65:7968–7975. 2005. View Article : Google Scholar : PubMed/NCBI

53 

Matsuo SE, Leoni SG, Colquhoun A and Kimura ET: Transforming growth factor-beta1 and activin A generate antiproliferative signaling in thyroid cancer cells. J Endocrinol. 190:141–150. 2006. View Article : Google Scholar : PubMed/NCBI

54 

Kaneda H, Arao T, Matsumoto K, De Velasco MA, Tamura D, Aomatsu K, Kudo K, Sakai K, Nagai T, Fujita Y, et al: Activin A inhibits vascular endothelial cell growth and suppresses tumour angiogenesis in gastric cancer. Br J Cancer. 105:1210–1217. 2011. View Article : Google Scholar : PubMed/NCBI

55 

Zonneville J, Safina A, Truskinovsky AM, Arteaga CL and Bakin AV: TGF-β signaling promotes tumor vasculature by enhancing the pericyte-endothelium association. BMC Cancer. 18:6702018. View Article : Google Scholar : PubMed/NCBI

56 

Furler RL, Nixon DF, Brantner CA, Popratiloff A and Uittenbogaart CH: TGF-β sustains tumor progression through biochemical and mechanical signal transduction. Cancers (Basel). 10(pii): E1992018. View Article : Google Scholar : PubMed/NCBI

57 

Miyazono K: Transforming growth factor-beta signaling in epithelial-mesenchymal transition and progression of cancer. Proc Jpn Acad Ser B Phys Biol Sci. 85:314–323. 2009. View Article : Google Scholar : PubMed/NCBI

58 

Hu B, An HM, Yan X, Zheng JL, Huang XW and Li M: Traditional Chinese medicine formulation Yanggan Jiedu Sanjie inhibits TGF-β1-induced epithelial-mesenchymal transition and metastatic potential in human hepatocarcinoma Bel-7402 cells. BMC Complement Altern Med. 19:672019. View Article : Google Scholar : PubMed/NCBI

59 

Yi EY, Park SY, Jung SY, Jang WJ and Kim YJ: Mitochondrial dysfunction induces EMT through the TGF-β/Smad/Snail signaling pathway in Hep3B hepatocellular carcinoma cells. Int J Oncol. 47:1845–1853. 2015. View Article : Google Scholar : PubMed/NCBI

60 

Zou G, Liu T, Guo L, Huang Y, Feng Y and Duan T: MicroRNA-32 silences WWP2 expression to maintain the pluripotency of human amniotic epithelial stem cells and β islet like cell differentiation. Int J Mol Med. 41:1983–1991. 2018.PubMed/NCBI

61 

Xu L, Long J, Shi C, Zhang N, Lv Y, Feng J, Xuan A, He X, Li Q, Bai Y, et al: Effect of leukocyte inhibitory factor on neuron differentiation from human induced pluripotent stem cell-derived neural precursor cells. Int J Mol Med. 41:2037–2049. 2018.PubMed/NCBI

62 

Murry CE and Keller G: Differentiation of embryonic stem cells to clinically relevant populations: Iessons from embryonic development. Cell. 132:661–680. 2008. View Article : Google Scholar : PubMed/NCBI

63 

Thomsen G, Woolf T, Whitman M, Sokol S, Vaughan J, Vale W and Melton DA: Activins are expressed early in Xenopus embryogenesis and can induce axial mesoderm and anterior structures. Cell. 63:485–493. 1990. View Article : Google Scholar : PubMed/NCBI

64 

Murata M, Eto Y, Shibai H, Sakai M and Muramatsu M: Erythroid differentiation factor is encoded by the same mRNA as that of the inhibin beta A chain. Proc Natl Acad Sci USA. 85:2434–2438. 1988. View Article : Google Scholar : PubMed/NCBI

65 

Bertacchi M, Lupo G, Pandolfini L, Casarosa S, D'Onofrio M, Pedersen RA, Harris WA and Cremisi F: Activin/Nodal signaling supports retinal progenitor specification in a narrow time window during pluripotent stem cell neuralization. Stem Cell Reports. 5:532–545. 2015. View Article : Google Scholar : PubMed/NCBI

66 

Davis AA, Matzuk MM and Reh TA: Activin A promotes progenitor differentiation into photoreceptors in rodent retina. Mol Cell Neurosci. 15:11–21. 2000. View Article : Google Scholar : PubMed/NCBI

67 

Vallier L, Mendjan S, Brown S, Chng Z, Teo A, Smithers LE, Trotter MW, Cho CH, Martinez A, Rugg-Gunn P, et al: Activin/Nodal signalling maintains pluripotency by controlling Nanog expression. Development. 136:1339–1349. 2009. View Article : Google Scholar : PubMed/NCBI

68 

Yang F, Wang N, Wang Y, Yu T and Wang H: Activin-SMAD signaling is required for maintenance of porcine iPS cell self-renewal through upregulation of NANOG and OCT4 expression. J Cell Physiol. 232:2253–2262. 2017. View Article : Google Scholar : PubMed/NCBI

69 

Gadue P, Huber TL, Paddison PJ and Keller GM: Wnt and TGF-beta signaling are required for the induction of an in vitro model of primitive streak formation using embryonic stem cells. Proc Natl Acad Sci USA. 103:16806–16811. 2006. View Article : Google Scholar : PubMed/NCBI

70 

Kattman SJ, Witty AD, Gagliardi M, Dubois NC, Niapour M, Hotta A, Ellis J and Keller G: Stage-specific optimization of activin/nodal and BMP signaling promotes cardiac differentiation of mouse and human pluripotent stem cell lines. Cell Stem Cell. 8:228–240. 2011. View Article : Google Scholar : PubMed/NCBI

71 

Toivonen S, Lundin K, Balboa D, Ustinov J, Tamminen K, Palgi J, Trokovic R, Tuuri T and Otonkoski T: Activin A and Wnt-dependent specification of human definitive endoderm cells. Exp Cell Res. 319:2535–2544. 2013. View Article : Google Scholar : PubMed/NCBI

72 

Duggal G, Heindryckx B, Warrier S, Taelman J, Van der Jeught M, Deforce D, Chuva de Sousa Lopes S and De Sutter P: Exogenous supplementation of Activin A enhances germ cell differentiation of human embryonic stem cells. Mol Hum Reprod. 21:410–423. 2015. View Article : Google Scholar : PubMed/NCBI

73 

Kubo A, Shinozaki K, Shannon JM, Kouskoff V, Kennedy M, Woo S, Fehling HJ and Keller G: Development of definitive endoderm from embryonic stem cells in culture. Development. 131:1651–1662. 2004. View Article : Google Scholar : PubMed/NCBI

74 

D'Amour KA, Agulnick AD, Eliazer S, Kelly OG, Kroon E and Baetge EE: Efficient differentiation of human embryonic stem cells to definitive endoderm. Nat Biotechnol. 23:1534–1541. 2005. View Article : Google Scholar : PubMed/NCBI

75 

Lu AQ, Popova EY and Barnstable CJ: Activin signals through Smad2/3 to increase photoreceptor precursor yield during embryonic stem cell differentiation. Stem Cell Reports. 9:838–852. 2017. View Article : Google Scholar : PubMed/NCBI

76 

Yang L, Soonpaa MH, Adler ED, Roepke TK, Kattman SJ, Kennedy M, Henckaerts E, Bonham K, Abbott GW, Linden RM, et al: Human cardiovascular progenitor cells develop from a KDR+embryonic-stem-cell-derived population. Nature. 453:524–528. 2008. View Article : Google Scholar : PubMed/NCBI

77 

Kim T, Echeagaray OH, Wang BJ, Casillas A, Broughton KM, Kim BH and Sussman MA: In situ transcriptome characteristics are lost following culture adaptation of adult cardiac stem cells. Sci Rep. 8:120602018. View Article : Google Scholar : PubMed/NCBI

78 

Cao L, Yang Y, Ye Z, Lin B, Zeng J, Li C, Liang T, Zhou K and Li J: Quercetin-3-methyl ether suppresses human breast cancer stem cell formation by inhibiting the Notch1 and PI3K/Akt signaling pathways. Int J Mol Med. 42:1625–1636. 2018.PubMed/NCBI

79 

Singh SK, Hawkins C, Clarke ID, Squire JA, Bayani J, Hide T, Henkelman RM, Cusimano MD and Dirks PB: Identification of human brain tumour initiating cells. Nature. 432:396–401. 2004. View Article : Google Scholar : PubMed/NCBI

80 

Spiller CM, Feng CW, Jackson A, Gillis AJ, Rolland AD, Looijenga LH, Koopman P and Bowles J: Endogenous Nodal signaling regulates germ cell potency during mammalian testis development. Development. 139:4123–4132. 2012. View Article : Google Scholar : PubMed/NCBI

81 

Ricci-Vitiani L, Lombardi DG, Pilozzi E, Biffoni M, Todaro M, Peschle C and De Maria R: Identification and expansion of human colon-cancer-initiating cells. Nature. 445:111–115. 2007. View Article : Google Scholar : PubMed/NCBI

82 

Coffin CM, Hornick JL and Fletcher CD: Inflammatory myofibroblastic tumor: Comparison of clinicopathologic, histologic, and immunohistochemical features including ALK expression in atypical and aggressive cases. Am J Surg Pathol. 31:509–520. 2017. View Article : Google Scholar

83 

David L, Mallet C, Mazerbourg S, Feige JJ and Bailly S: Identification of BMP9 and BMP10 as functional activators of the orphan activin receptor-like kinase 1 (ALK1) in endothelial cells. Blood. 109:1953–1961. 2007. View Article : Google Scholar : PubMed/NCBI

84 

de Vinuesa AG, Bocci M, Pietras K and Ten Dijke P: Targeting tumour vasculature by inhibiting activin receptor-like kinase (ALK) 1 function. Biochem Soc Trans. 44:1142–1149. 2016. View Article : Google Scholar : PubMed/NCBI

85 

Goff LW, Cohen RB, Berlin JD, de Braud FG, Lyshchik A, Noberasco C, Bertolini F, Carpentieri M, Stampino CG, Abbattista A, et al: A phase I study of the anti-activin receptor-like kinase 1 (ALK-1) monoclonal antibody PF-03446962 in patients with advanced solid tumors. Clin Cancer Res. 22:2146–2154. 2016. View Article : Google Scholar : PubMed/NCBI

86 

Burger RA, Deng W, Makker V, Collins Y, Gray H, Debernardo R, Martin LP and Aghajanian C: Phase II evaluation of dalantercept in the treatment of persistent or recurrent epithelial ovarian cancer: An NRG Oncology/Gynecologic Oncology Group study. Gynecol Oncol. 150:466–470. 2018. View Article : Google Scholar : PubMed/NCBI

87 

Cunha SI, Pardali E, Thorikay M, Anderberg C, Hawinkels L, Goumans MJ, Seehra J, Heldin CH, Ten Dijke P and Pietras K: Genetic and pharmacological targeting of activin receptor-like kinase 1 impairs tumor growth and angiogenesis. J Exp Med. 207:85–100. 2010. View Article : Google Scholar : PubMed/NCBI

88 

Herrera B, Garcia-Álvaro M, Cruz S, Walsh P, Fernández M, Roncero C, Fabregat I, Sánchez A and Inman GJ: BMP9 is a proliferative and survival factor for human hepatocellular carcinoma cells. PLoS One. 8:e695352013. View Article : Google Scholar : PubMed/NCBI

89 

Li Q, Gu X, Weng H, Ghafoory S, Liu Y, Feng T, Dzieran J, Li L, Ilkavets I, Kruithof-de Julio M, et al: Bone morphogenetic protein-9 induces epithelial to mesenchymal transition in hepatocellular carcinoma cells. Cancer Sci. 104:398–408. 2013. View Article : Google Scholar : PubMed/NCBI

90 

Suzuki Y, Ohga N, Morishita Y, Hida K, Miyazono K and Watabe T: BMP-9 induces proliferation of multiple typese of endothelial cells in vitro and in vivo. J Cell Sci. 123:1684–1692. 2010. View Article : Google Scholar : PubMed/NCBI

91 

Machiya A, Tsukamoto S, Ohte S, Kuratani M, Fujimoto M, Kumagai K, Osawa K, Suda N, Bullock AN and Katagiri T: Effects of FKBP12 and type II BMP receptors on signal transduction by ALK2 activating mutations associated with genetic disorders. Bone. 111:101–108. 2018. View Article : Google Scholar : PubMed/NCBI

92 

Macías-Silva M, Hoodless PA, Tang SJ, Buchwald M and Wrana JL: Specific activation of Smad1 signaling pathways by the BMP7 type I receptor, ALK2. J Biol Chem. 273:25628–25636. 1998. View Article : Google Scholar : PubMed/NCBI

93 

Kim M, Choi O, Pyo S, Choi SU and Park CH: Identification of novel ALK2 inhibitors and their effect on cancer cells. Biochem Biophys Res Commun. 492:121–127. 2017. View Article : Google Scholar : PubMed/NCBI

94 

Zhang L, Wang H, Yu D, Chen J, Xing C, Li J, Li J and Cai Y: The effects of mouse ovarian granulosa cell function and related gene expression by suppressing BMP/Smad signaling pathway. Anim Cells Syst (Seoul). 22:317–323. 2018. View Article : Google Scholar : PubMed/NCBI

95 

Zhou Y, Sun H, Danila DC, Johnson SR, Sigai DP, Zhang X and Klibanski A: Truncated activin type I receptor Alk4 isoforms are dominant negative receptors inhibiting activin signaling. Mol Endocrinol. 14:2066–2075. 2000. View Article : Google Scholar : PubMed/NCBI

96 

Danila DC, Zhang X, Zhou Y, Haidar JN and Klibanski A: Overexpression of wild-type activin receptor alk4-1 restores activin antiproliferative effects in human pituitary tumor cells. J Clin Endocrinol Metab. 87:4741–4746. 2002. View Article : Google Scholar : PubMed/NCBI

97 

Jeruss JS, Sturgis CD, Rademaker AW and Woodruff TK: Down-regulation of activin, activin receptors, and smads in high-grade breast cancer. Cancer Res. 63:3783–3790. 2003.PubMed/NCBI

98 

Rodon J, Carducci MA, Sepulveda-Sánchez JM, Azaro A, Calvo E, Seoane J, Braña I, Sicart E, Gueorguieva I, Cleverly AL, et al: First-in-human dose study of the novel transforming growth factor-β receptor I kinase inhibitor LY2157299 monohydrate in patients with advanced cancer and glioma. Clin Cancer Res. 21:553–560. 2015. View Article : Google Scholar : PubMed/NCBI

99 

Fransvea E, Angelotti U, Antonaci S and Giannelli G: Blocking transforming growth factor-beta up-regulates E-cadherin and reduces migration and invasion of hepatocellular carcinoma cells. Hepatology. 47:1557–1566. 2008. View Article : Google Scholar : PubMed/NCBI

100 

Mazzocca A, Fransvea E, Dituri F, Lupo L, Antonaci S and Giannelli GL: Down-regulation of connective tissue growth factor by inhibition of transforming growth factor beta blocks the tumor-stroma cross-talk and tumor progression in hepatocellular carcinoma. Hepatology. 51:523–534. 2010. View Article : Google Scholar : PubMed/NCBI

101 

Kim IY, Ahn HJ, Zelner DJ, Shaw JW, Sensibar JA, Kim JH, Kato M and Lee C: Genetic change in transforming growth factor beta (TGF-beta) receptor type I gene correlates with insensitivity to TGF-beta 1 in human prostate cancer cells. Cancer Res. 56:44–48. 1996.PubMed/NCBI

102 

Kim IY, Ahn HJ, Lang S, Oefelein MG, Oyasu R, Kozlowski JM and Lee C: Loss of expression of transforming growth factor-beta receptors is associated with poor prognosis in prostate cancer patients. Clin Cancer Res. 4:1625–1630. 1998.PubMed/NCBI

103 

Singh J, Ling LE, Sawyer JS, Lee WC, Zhang F and Yingling JM: Transforming the TGFbeta pathway: Convergence of distinct lead generation strategies on a novel kinase pharmacophore for TbetaRI (ALK5). Curr Opin Drug Discov Devel. 7:437–445. 2004.PubMed/NCBI

104 

Shinriki S, Jono H, Maeshiro M, Nakamura T, Guo J, Li JD, Ueda M, Yoshida R, Shinohara M, Nakayama H, et al: Loss of CYLD promotes cell invasion via ALK5 stabilization in oral squamous cell carcinoma. J Pathol. 244:367–379. 2018. View Article : Google Scholar : PubMed/NCBI

105 

Zeddou M, Relic B, Malaise O, Charlier E, Desoroux A, Beguin Y, de Seny D and Malaise MG: Differential signalling through ALK-1 and ALK-5 regulates leptin expression in mesenchymal stem cells. Stem Cells Dev. 21:1948–1955. 2012. View Article : Google Scholar : PubMed/NCBI

106 

de Kroon LM, Narcisi R, Blaney Davidson EN, Cleary MA, van Beuningen HM, Koevoet WJ, van Osch GJ and van der Kraan PM: Activin receptor-like kinase receptors ALK5 and ALK1 are both required for TGFβ-induced chondrogenic differentiation of human bone marrow-derived mesenchymal stem cells. PLoS One. 10:e01461242015. View Article : Google Scholar : PubMed/NCBI

107 

Hatsell SJ, Idone V, Wolken DM, Huang L, Kim HJ, Wang L, Wen X, Nannuru KC, Jimenez J, Xie L, et al: ACVR1R206H receptor mutation causes fibrodysplasia ossificans progressiva by imparting responsiveness to activin A. Sci Transl Med. 7:303ra1372015. View Article : Google Scholar : PubMed/NCBI

108 

Lin H, Ying Y, Wang YY, Jiang SS, Huang D, Luo L, Chen YG, Gerstenfeld LC and Luo Z: AMPK downregulates ALK2 via increasing the interaction between Smurf1 and Smad6, leading to inhibition of osteogenic differentiation. Biochim Biophys Acta Mol Cell Res. 1864:2369–2377. 2017. View Article : Google Scholar : PubMed/NCBI

109 

Lin T, Ambasudhan R, Yuan X, Li W, Hilcove S, Abujarour R, Lin X, Hahm HS, Hao E, Hayek A and Ding S: A chemical platform for improved induction of human iPSCs. Nature Methods. 6:805–808. 2009. View Article : Google Scholar : PubMed/NCBI

110 

Laping NJ, Grygielko E, Mathur A, Butter S, Bomberger J, Tweed C, Martin W, Fornwald J, Lehr R, Harling J, et al: Inhibition of transforming growth factor (TGF)-beta1-induced extracellular matrix with a novel inhibitor of the TGF-beta type I receptor kinase activity: SB-431542. Mol Pharmacol. 62:58–64. 2002. View Article : Google Scholar : PubMed/NCBI

111 

Inman GJ, Nicolás FJ, Callahan JF, Harling JD, Gaster LM, Reith AD, Laping NJ and Hill CS: SB-431542 is a potent and specific inhibitor of transforming growth factor-beta superfamily type I activin receptor-like kinase (ALK) receptors ALK4, ALK5, and ALK7. Mol Pharmacol. 62:65–74. 2002. View Article : Google Scholar : PubMed/NCBI

112 

Tojo M, Hamashima Y, Hanyu A, Kajimoto T, Saitoh M, Miyazono K, Node M and Imamura T: The ALK-5 inhibitor A-83-01 inhibits Smad signaling and epithelial-to-mesenchymal transition by transforming growth factor-beta. Cancer Sci. 96:791–800. 2005. View Article : Google Scholar : PubMed/NCBI

113 

Li W, Wei W, Zhu S, Zhu J, Shi Y, Lin T, Hao E, Hayek A, Deng H and Ding S: Generation of rat and human induced pluripotent stem cells by combining genetic reprogramming and chemical inhibitors. Cell Stem Cell. 4:16–19. 2009. View Article : Google Scholar : PubMed/NCBI

114 

Klincumhom N, Tharasanit T, Thongkittidilok C, Tiptanavattana N, Rungarunlert S, Dinnyés A and Techakumphu M: Selective TGF-β1/ALK inhibitor improves neuronal differentiation of mouse embryonic stem cells. Neurosci Lett. 578:1–6. 2014. View Article : Google Scholar : PubMed/NCBI

115 

Halder SK, Beauchamp RD and Datta PK: A specific inhibitor of TGF-beta receptor kinase, SB-431542, as a potent antitumor agent for human cancers. Neoplasia. 7:509–521. 2005. View Article : Google Scholar : PubMed/NCBI

116 

Matsuyama S, Iwadate M, Kondo M, Saitoh M, Hanyu A, Shimizu K, Aburatani H, Mishima HK, Imamura T, Miyazono K and Miyazawa K: SB-431542 and Gleevec inhibit transforming growth factor-beta-induced proliferation of human osteosarcoma cells. Cancer Res. 63:7791–7798. 2003.PubMed/NCBI

117 

Sato M, Matsubara T, Adachi J, Hashimoto Y, Fukamizu K, Kishida M, Yang YA, Wakefield LM and Tomonaga T: Differential proteome analysis identifies TGF-β-related pro-metastatic proteins in a 4T1 murine breast cancer model. PLoS One. 10:e01264832015. View Article : Google Scholar : PubMed/NCBI

118 

Kim BH, Guardia Clausi M, Frondelli M, Nnah IC, Saqcena C, Dobrowolski R and Levison SW: Age-dependent effects of ALK5 inhibition and mechanism of neuroprotection in neonatal hypoxic-ischemic brain injury. Dev Neurosci. 39:338–351. 2017. View Article : Google Scholar : PubMed/NCBI

119 

Wang XB, Zhu H, Song W and Su JH: Gremlin regulates podocyte apoptosis via transforming growth factor-β (TGF-β) pathway in diabetic nephropathy. Med Sci Monit. 24:183–189. 2018. View Article : Google Scholar : PubMed/NCBI

120 

Grygielko ET, Martin WM, Tweed C, Thornton P, Harling J, Brooks DP and Laping NJ: Inhibition of gene markers of fibrosis with a novel inhibitor of transforming growth factor-beta type I receptor kinase in puromycin-induced nephritis. J Pharmacol Exp Ther. 313:943–951. 2005. View Article : Google Scholar : PubMed/NCBI

121 

Xu H, Yang F, Sun Y, Yuan Y, Cheng H, Wei Z, Li S, Cheng T, Brann D and Wang R: A new antifibrotic target of Ac-SDKP: Inhibition of myofibroblast differentiation in rat lung with silicosis. PLoS One. 7:e403012012. View Article : Google Scholar : PubMed/NCBI

122 

Gauger KJ, Chenausky KL, Murray ME and Schneider SS: SFRP1 reduction results in an increased sensitivity to TGF-β signaling. BMC Cancer. 11:592011. View Article : Google Scholar : PubMed/NCBI

123 

Kimura-Kuroda J, Teng X, Komuta Y, Yoshioka N, Sango K, Kawamura K, Raisman G and Kawano H: An in vitro model of the inhibition of axon growth in the lesion scar formed after central nervous system injury. Mol Cell Neurosci. 43:177–187. 2010. View Article : Google Scholar : PubMed/NCBI

124 

Giannelli G, Villa E and Lahn M: Transforming growth factor-β as a therapeutic target in hepatocellular carcinoma. Cancer Res. 74:1890–1894. 2014. View Article : Google Scholar : PubMed/NCBI

125 

Bueno L, de Alwis DP, Pitou C, Yingling J, Lahn M, Glatt S and Trocóniz IF: Semi-mechanistic modelling of the tumour growth inhibitory effects of LY2157299, a new type I receptor TGF-beta kinase antagonist, in mice. Eur J Cancer. 44:142–150. 2008. View Article : Google Scholar : PubMed/NCBI

126 

de Gouville AC, Boullay V, Krysa G, Pilot J, Brusq JM, Loriolle F, Gauthier JM, Papworth SA, Laroze A, Gellibert F and Huet S: Inhibition of TGF-beta signaling by an ALK5 inhibitor protects rats from dimethylnitrosamine-induced liver fibrosis. Br J Pharmacol. 145:166–177. 2005. View Article : Google Scholar : PubMed/NCBI

127 

Leung SY, Niimi A, Noble A, Oates T, Williams AS, Medicherla S, Protter AA and Chung KF: Effect of transforming growth factor-beta receptor I kinase inhibitor 2,4-disubstituted pteridine (SD-208) in chronic allergic airway inflammation and remodeling. J Pharmacol Exp Ther. 319:586–594. 2006. View Article : Google Scholar : PubMed/NCBI

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June 2019
Volume 19 Issue 6

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APA
Cui, X., Shang, S., Lv, X., Zhao, J., Qi, Y., & Liu, Z. (2019). Perspectives of small molecule inhibitors of activin receptor‑like kinase in anti‑tumor treatment and stem cell differentiation (Review). Molecular Medicine Reports, 19, 5053-5062. https://doi.org/10.3892/mmr.2019.10209
MLA
Cui, X., Shang, S., Lv, X., Zhao, J., Qi, Y., Liu, Z."Perspectives of small molecule inhibitors of activin receptor‑like kinase in anti‑tumor treatment and stem cell differentiation (Review)". Molecular Medicine Reports 19.6 (2019): 5053-5062.
Chicago
Cui, X., Shang, S., Lv, X., Zhao, J., Qi, Y., Liu, Z."Perspectives of small molecule inhibitors of activin receptor‑like kinase in anti‑tumor treatment and stem cell differentiation (Review)". Molecular Medicine Reports 19, no. 6 (2019): 5053-5062. https://doi.org/10.3892/mmr.2019.10209