Top

Published in:

01-12-2010 | Research Paper

Actin-sequestering protein, thymosin beta-4, is a novel hypoxia responsive regulator

Authors: Eun-Yi Moon, Yun-Sun Im, Yun-Kyoung Ryu, Joo-Hyun Kang

Published in: Clinical & Experimental Metastasis | Issue 8/2010

Abstract

Angiogenesis is induced by soluble factors such as vascular endothelial growth factor (VEGF) released from tumor cells in hypoxia. It enhances solid tumor growth and provides an ability to establish metastasis at peripheral sites by tumor cell migration. Thymosin beta-4 (TB4) is an actin-sequestering protein to control cytoskeletal reorganization. Here, we investigated whether angiogenesis and tumor metastasis are dependent on hypoxia conditioning-induced TB4 expression in B16F10 melanoma cells. TB4 expression in B16F10 cells was increased by hypoxia conditioning in a time-dependent manner. In addition, we found an increase of angiogenesis and HIF-1α expression in TB4-transgenic (Tg) mice as compared to wildtype mice. When wound healing assay was used to assess in vitro tumor cell migration, hypoxia conditioning for 1 h enhanced B16F10 cell migration. When TB4 expression in B16F10 cells was inhibited by the infection with small hairpin (sh) RNA of TB4 cloned in lentiviral vector, tumor cell migration was retarded. In addition, hypoxia conditioning-induced tumor cell migration was reduced by the infection of lentiviral shRNA of TB4. HIF-1α stabilization and the expression of VEGF isoform 165 and 121 in hypoxia were also reduced by the infection of lentiviral shRNA of TB4 in B16F10 cells. We also found an increase of tumor growth and lung metastasis count in TB4-Tg mice as compared to wildtype mice. Collectively, hypoxia conditioning induced tumor cell migration by TB4 expression-dependent HIF-1α stabilization. It suggests that TB4 could be a hypoxia responsive regulator to control tumor cell migration in angiogenesis and tumor metastasis.

Huff T, Muller CS, Otto AM et al (2001) Beta-thymosins, small acidic peptides with multiple functions. Int J Biochem Cell Biol 33:205–220CrossRefPubMed

Domanski M, Hertzog M, Coutant J et al (2004) Coupling of folding and binding of thymosin beta4 upon interaction with monomeric actin monitored by nuclear magnetic resonance. J Biol Chem 279:23637–23645CrossRefPubMed

Hertzog M, van Heijenoort C, Didry D et al (2004) The beta-thymosin/WH2 domain; structural basis for the switch from inhibition to promotion of actin assembly. Cell 117:611–623CrossRefPubMed

Cha HJ, Jeong MJ, Kleinman HK (2003) Role of thymosin beta4 in tumor metastasis and angiogenesis. J Natl Cancer Inst 95:1674–1680PubMed

Goldstein AL (2003) Thymosin beta4: a new molecular target for antitumor strategies. J Natl Cancer Inst 95:1646–1647PubMed

Sosne G, Siddiqi A, Kurpakus-Wheater M (2004) Thymosin-beta4 inhibits corneal epithelial cell apoptosis after ethanol exposure in vitro. Invest Ophthalmol Vis Sci 45:1095–1100CrossRefPubMed

Oh SY, Song JH, Gil JE et al (2006) ERK activation by thymosin-beta-4 (TB4) overexpression induces paclitaxel-resistance. Exp Cell Res 312:1651–1657CrossRefPubMed

Oh JM, Ryoo IJ, Yang Y et al (2008) Hypoxia-inducible transcription factor (HIF)-1 alpha stabilization by actin-sequestering protein, thymosin beta-4 (TB4) in Hela cervical tumor cells. Cancer Lett 264:29–35CrossRefPubMed

Wang GL, Jiang BH, Rue EA et al (1995) Hypoxia-inducible factor 1 is a basic-helix-loop-helix-PAS heterodimer regulated by cellular O2 tension. Proc Natl Acad Sci USA 92:5510–5514CrossRefPubMed

10.

Folkman J (1990) What is the evidence that tumors are angiogenesis dependent? J Natl Cancer Inst 82:4–6CrossRefPubMed

11.

Dong JEH, Shin CY (2008) Vasorelaxing effect of hypoxia via Rho-kinase inhibition on the agonist-specific vasoconstriction. Biomol Ther 16:249–254CrossRef

12.

Ke Q, Costa M (2006) Hypoxia-inducible factor-1 (HIF-1). Mol Pharmacol 70:1469–1480CrossRefPubMed

13.

Huang LE, Gu J, Schau M et al (1998) Regulation of hypoxia-inducible factor 1alpha is mediated by an O2-dependent degradation domain via the ubiquitin-proteasome pathway. Proc Natl Acad Sci USA 95:7987–7992CrossRefPubMed

14.

Zhang T, Li X, Yu W et al (2009) Overexpression of thymosin beta-10 inhibits VEGF mRNA expression, autocrine VEGF protein production, and tube formation in hypoxia-induced monkey choroid-retinal endothelial cells. Ophthalmic Res 41:36–43CrossRefPubMed

15.

Ferrara N, Houck K, Jakeman L et al (1992) Molecular and biological properties of the vascular endothelial growth factor family of proteins. Endocr Rev 13:18–32PubMed

16.

Houck KA, Ferrara N, Winer J et al (1991) The vascular endothelial growth factor family: identification of a fourth molecular species and characterization of alternative splicing of RNA. Mol Endocrinol 5:1806–1814CrossRefPubMed

17.

White FC, Carroll SM, Kamps MP (1995) VEGF mRNA is reversibly stabilized by hypoxia and persistently stabilized in VEGF-overexpressing human tumor cell lines. Growth Factors 12:289–301CrossRefPubMed

18.

Gunningham SP, Currie MJ, Han C et al (2001) Vascular endothelial growth factor-B and vascular endothelial growth factor-C expression in renal cell carcinomas: regulation by the von Hippel-Lindau gene and hypoxia. Cancer Res 61:3206–3211PubMed

19.

Singer SJ, Kupfer A (1986) The directed migration of eukaryotic cells. Annu Rev Cell Biol 2:337–365CrossRefPubMed

20.

Park SY, Jeong KJ, Lee J et al (2007) Hypoxia enhances LPA-induced HIF-1alpha and VEGF expression: their inhibition by resveratrol. Cancer Lett 258:63–69CrossRefPubMed

21.

Jiang M, Wang B, Wang C et al (2006) Inhibition of hypoxia-inducible factor-1alpha and endothelial progenitor cell differentiation by adenoviral transfer of small interfering RNA in vitro. J Vasc Res 43:511–521CrossRefPubMed

22.

Lin S, Sun L, Hu J et al (2009) Chemokine C-X-C motif receptor 6 contributes to cell migration during hypoxia. Cancer Lett 279:108–117CrossRefPubMed

23.

Semenza GL (2000) HIF-1: using two hands to flip the angiogenic switch. Cancer Metastasis Rev 19:59–65CrossRefPubMed

24.

Yu DY, Moon HB, Son JK et al (1999) Incidence of hepatocellular carcinoma in transgenic mice expressing the hepatitis B virus X-protein. J Hepatol 31:123–132CrossRefPubMed

25.

Follenzi A, Ailles LE, Bakovic S et al (2000) Gene transfer by lentiviral vectors is limited by nuclear translocation and rescued by HIV-1 pol sequences. Nat Genet 25:217–222CrossRefPubMed

26.

Dull T, Zufferey R, Kelly M (1998) A third-generation lentivirus vector with a conditional packaging system. J Virol 72:8463–8471PubMed

27.

Drabkin DS, Austin JH et al (1932) Spectrophotometric constants for common hemoglobin derivatives in human, dog, and rabbit blood. J Biol Chem 98:719–733

28.

Borisy GG, Svitkina TM (2000) Actin machinery: pushing the envelope. Curr Opin Cell Biol 12:104–112CrossRefPubMed

29.

Pantaloni D, Le Clainche C, Carlier MF (2001) Mechanism of actin-based motility. Science 292:1502–1506CrossRefPubMed

30.

Turcotte S, Desrosiers RR, Beliveau R (2003) HIF-1alpha mRNA and protein upregulation involves Rho GTPase expression during hypoxia in renal cell carcinoma. J Cell Sci 116:2247–2260CrossRefPubMed

31.

Safer D, Nachmias VT (1994) Beta thymosins as actin binding peptides. Bioessays 16:473–479CrossRefPubMed

32.

Michiels C, Minet E, Michel G et al (2001) HIF-1 and AP-1 cooperate to increase gene expression in hypoxia: role of MAP kinases. IUBMB Life 52:49–53CrossRefPubMed

33.

Mottet D, Michel G, Renard P et al (2002) ERK and calcium in activation of HIF-1. Ann N Y Acad Sci 973:448–453CrossRefPubMed

34.

Mottet D, Michel G, Renard P et al (2003) Role of ERK and calcium in the hypoxia-induced activation of HIF-1. J Cell Physiol 194:30–44CrossRefPubMed

35.

Minet E, Arnould T, Michel G et al (2000) ERK activation upon hypoxia: involvement in HIF-1 activation. FEBS Lett 468:53–58CrossRefPubMed

36.

Huang HC, Hu CH, Tang MC et al (2007) Thymosin beta4 triggers an epithelial-mesenchymal transition in colorectal carcinoma by upregulating integrin-linked kinase. Oncogene 26:2781–2790CrossRefPubMed

Title: Actin-sequestering protein, thymosin beta-4, is a novel hypoxia responsive regulator
Authors: Eun-Yi Moon
Yun-Sun Im
Yun-Kyoung Ryu
Joo-Hyun Kang
Publication date: 01-12-2010
Publisher: Springer Netherlands
Published in: Clinical & Experimental Metastasis / Issue 8/2010
Print ISSN: 0262-0898
Electronic ISSN: 1573-7276
DOI: https://doi.org/10.1007/s10585-010-9350-z

Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras

Prof. Fabrice Barlesi

Developed by: Springer Medicine

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Please log in to get access to this content

Other articles of this Issue 8/2010

Serum follistatin in patients with prostate cancer metastatic to the bone

Effects of dietary fat on spontaneous metastasis of Lewis lung carcinoma in mice

Co-expression of CD147/EMMPRIN with monocarboxylate transporters and multiple drug resistance proteins is associated with epithelial ovarian cancer progression

KISS1 over-expression suppresses metastasis of pancreatic adenocarcinoma in a xenograft mouse model

p-AKT overexpression in primary renal cell carcinomas and their metastases

Mesenchymal mode of migration participates in pulmonary metastasis of mouse osteosarcoma LM8

Keynote webinar | Spotlight on antibody–drug conjugates in cancer