Rosiglitazone suppresses angiogenesis in multiple myeloma via downregulation of hypoxia‑inducible factor‑1α and insulin‑like growth factor‑1 mRNA expression

Rui,Mingzhong; Huang,Zhanping; Liu,Ying; Wang,Ziyan; Liu,Rui; Fu,Jinxiang; Huang,Haiwen

doi:10.3892/mmr.2014.2407

Rosiglitazone suppresses angiogenesis in multiple myeloma via downregulation of hypoxia‑inducible factor‑1α and insulin‑like growth factor‑1 mRNA expression

Authors:
- Mingzhong Rui
- Zhanping Huang
- Ying Liu
- Ziyan Wang
- Rui Liu
- Jinxiang Fu
- Haiwen Huang
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Affiliations: Department of Hematology, The Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215004, P.R. China
Published online on: July 22, 2014 https://doi.org/10.3892/mmr.2014.2407
Pages: 2137-2143

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Abstract

Rosiglitazone (RGZ) is a thiazolidinedione ligand of peroxisome proliferator‑activated receptor‑γ. Our previous studies have confirmed that RGZ possesses antitumoral properties. Bone marrow angiogenesis exhibits an important role in multiple myeloma (MM), and angiogenesis often correlates with the prognosis and disease burden of MM. However, to the best of our knowledge, inhibition of angiopoiesis by RGZ in MM has not yet been reported. The present study aimed to investigate whether RGZ prevents angiogenesis and the possible underlying mechanism of this effect in MM. RPMI‑8226 cells, primary myeloma cells from patients with MM or mononuclear cells from healthy patients were treated with different concentrations of RGZ, and various biological responses were detected using MTT, reverse transcription‑polymerase chain reaction and western blot assays. The expression levels of hypoxia‑inducible transcription factor‑1α (HIF1α) and insulin‑like growth factor‑1 (IGF1) were significantly increased in the RPMI‑8226 cells and the primary myeloma cells from the patients with MM compared with those in the mononuclear cells from the healthy patients. The results also showed that RGZ was able to inhibit proliferation and reduce viability of RPMI‑8226 cells in a concentration‑ and time‑dependent manner. RGZ was able to concentration‑dependently inhibit the expression of HIF1α and IGF1 mRNA in RPMI‑8226 and primary myeloma cells from patients with MM. RGZ also inhibited the expression of pAKT and downregulated the expression levels of phosphorylated extracellular signal‑regulated kinase (ERK) in RPMI‑8226 cells. The results suggested that RGZ inhibits the angiopoiesis of tumors by interfering with the phosphatidylinositol 3‑kinase/AKT and ERK signaling pathways.

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1	Rajkumar SV: Treatment of multiple myeloma. Nat Rev Clin Oncol. 8:479–491. 2011. View Article : Google Scholar
2	Ribatti D, Vacca A, Dammacco F and English D: Angiogenesis and anti-angiogenesis in hematological malignancies. J Hematother Stem Cell Res. 12:11–22. 2003. View Article : Google Scholar
3	Ribatti D, Nico B and Vacca A: Importance of the bone marrow microenvironment in inducing the angiogenic response in multiple myeloma. Oncogene. 25:4257–4266. 2006. View Article : Google Scholar : PubMed/NCBI
4	Giatromanolaki A, Bai M, Margaritis D, et al: Hypoxia and activated VEGF/receptor pathway in multiple myeloma. Anticancer Res. 30:2831–2836. 2010.PubMed/NCBI
5	Martin SK, Diamond P, Williams SA, et al: Hypoxia-inducible factor-2 is a novel regulator of aberrant CXCL12 expression in multiple myeloma plasma cells. Haematologica. 95:776–784. 2010. View Article : Google Scholar : PubMed/NCBI
6	Colla S, Storti P, Donofrio G, et al: Low bone marrow oxygen tension and hypoxia-inducible factor-1α overexpression characterize patients with multiple myeloma: role on the transcriptional and proangiogenic profiles of CD138(+) cells. Leukemia. 24:1967–1970. 2010.
7	Zhang J, Sattler M, Tonon G, et al: Targeting angiogenesis via a c-Myc/hypoxia-inducible factor-1alpha-dependent pathway in multiple myeloma. Cancer Res. 69:5082–5090. 2009. View Article : Google Scholar : PubMed/NCBI
8	Menu E, Jernberg-Wiklund H, De Raeve H, et al: Targeting the IGF-1R using picropodophyllin in the therapeutical 5T2MM mouse model of multiple myeloma: beneficial effects on tumor growth, angiogenesis, bone disease and survival. Int J Cancer. 121:1857–1861. 2007. View Article : Google Scholar
9	Menu E, van Valckenborgh E, van Camp B and Vanderkerken K: The role of the insulin-like growth factor 1 receptor axis in multiple myeloma. Arch Physiol Biochem. 115:49–57. 2009. View Article : Google Scholar : PubMed/NCBI
10	Pappa CA, Tsirakis G, Psarakis FE, Kolovou A, Tsigaridaki M, Stafylaki D, Sfiridaki K and Alexandrakis MG: Lack of correlation between angiogenic cytokines and serum insulin-like growth factor-1 in patients with multiple myeloma. Med Oncol. Mar;30:3632013. View Article : Google Scholar : PubMed/NCBI
11	Stoeltzing O, Liu W, Reinmuth N, et al: Regulation of hypoxia-inducible factor-1alpha, vascular endothelial growth factor, and angiogenesis by an insulin-like growth factor-I receptor autocrine loop in human pancreatic cancer. Am J Pathol. 163:1001–1011. 2003. View Article : Google Scholar
12	Fukuda R, Hirota K, Fan F, et al: Insulin-like growth factor 1 induces hypoxia-inducible factor1-mediated vascular endothelial growth factor expression, which is dependent on MAP kinase and phosphatidylinositol 3-kinase signaling in colon cancer cells. J Biol Chem. 277:38205–38211. 2002. View Article : Google Scholar
13	Treins C, Giorgetti-Peraldi S, Murdaca J, et al: Regulation of hypoxia-inducible factor (HIF)-1 activity and expression of HIF hydroxylases in response to insulin-like growth factor I. Mol Endocrinol. 19:1304–1317. 2005. View Article : Google Scholar : PubMed/NCBI
14	Menu E, Kooijman R, Van Valckenborgh E, et al: Specific roles for the PI3K and the MEK-ERK pathway in IGF-1-stimulated chemotaxis, VEGF secretion and proliferation of multiple myeloma cells: study in the 5T33MM model. Br J Cancer. 90:1076–1083. 2004. View Article : Google Scholar
15	Poulaki V, Mitsiades CS, McMullan C, et al: Regulation of vascular endothelial growth factor expression by insulin-like growth factor I in thyroid carcinomas. J Clin Endocrinol Metab. 88:5392–5398. 2003. View Article : Google Scholar : PubMed/NCBI
16	Sang N, Stiehl DP, Bohensky J, Leshchinsky I, Srinivas V and Caro J: MAPK signaling up-regulates the activity of hypoxia-inducible factors by its effects on p300. J Biol Chem. 278:14013–14019. 2003. View Article : Google Scholar : PubMed/NCBI
17	Minet E, Arnould T, Michel G, Roland I, Mottet D, Raes M, Remacle J and Michiels C: ERK activation upon hypoxia: involvement in HIF-1 activation. FEBS Lett. 468:53–58. 2000. View Article : Google Scholar : PubMed/NCBI
18	Shi YH, Wang YX, Bingle L, Gong LH, Heng WJ, Li Y and Fang WG: In vitro study of HIF-1 activation and VEGF release by bFGF in the T47D breast cancer cell line under normoxic conditions: involvement of PI-3K/Akt and MEK1/ERK pathways. J Pathol. 205:530–536. 2005. View Article : Google Scholar : PubMed/NCBI
19	Huang H, Wu D, Fu J, Chen G, Chang W, Chow HC, Leung AY and Liang R: All-trans retinoic acid can intensify the growth inhibition and differentiation induction effect of rosiglitazone on multiple myeloma cells. Eur J Haematol. 83:191–202. 2009. View Article : Google Scholar
20	Lecka-Czernik B, Ackert-Bicknell C, Adamo ML, et al: Activation of peroxisome proliferator-activated receptor gamma (PPARgamma) by rosiglitazone suppresses components of the insulin-like growth factor regulatory system in vitro and in vivo. Endocrinology. 148:903–911. 2007. View Article : Google Scholar
21	Kang BY, Kleinhenz JM, Murphy TC and Hart CM: The PPARγ ligand rosiglitazone attenuates hypoxia-induced endothelin signaling in vitro and in vivo. Am J Physiol Lung Cell Mol Physiol. 301:L881–L891. 2011.
22	Nickkho-Amiry M, McVey R and Holland C: Peroxisome proliferator activated receptors modulate proliferation and angiogenesis in human endometrial carcinoma. Mol Cancer Res. 10:441–453. 2012. View Article : Google Scholar
23	Yokoyama Y, Xin B, Shigeto T and Mizunuma H: Combination of ciglitazone, a peroxisome proliferator activated receptor gamma ligand, and cisplatin enhances the inhibition of growth of human ovarian cancers. J Cancer Res Clin Oncol. 137:1219–1228. 2011. View Article : Google Scholar
24	Reka AK, Goswami MT, Krishnapuram R, Standiford TJ and Keshamouni VG: Molecular cross-regulation between PPAR-γ and other signaling pathways: implications for lung cancer therapy. Lung Cancer. 72:154–159. 2011.
25	Dong YW, Wang XP and Wu K: Suppression of pancreatic carcinoma growth by activating peroxisome proliferator-activated receptor gamma involves angiogenesis inhibition. World J Gastroenterol. 15:441–448. 2009. View Article : Google Scholar
26	Kim KY, Ahn JH and Cheon HG: Anti-angiogenic action of PPARγ ligand in human umbilical vein endothelial cells is mediated by PTEN upregulation and VEGFR-2 downregulation. Mol Cell Biochem. 358:375–385. 2011.
27	Weidner N, Folkman J, Pozza F, Bevilacqua P, Allred EN, Moore DH, Meli S and Gasparini G: Tumor angiogenesis: a new significant and independent prognostic indicator in early-stage breast carcinoma. J Natl Cancer Inst. 84:1875–1887. 1992. View Article : Google Scholar : PubMed/NCBI
28	Bertolini F, Mancuso P, Gobbi A and Pruneri G: The thin red line: angiogenesis in normal and malignant hematopoiesis. Exp Hematol. 28:993–1000. 2000. View Article : Google Scholar : PubMed/NCBI
29	Bhaskar A, Gupta R, Vishnubhatla S, Kumar L, Sharma A, Sharma MC, Das P and Thakur SC: Angiopoietins as biomarker of disease activity and response to therapy in multiple myeloma. Leuk Lymphoma. 54:1473–1478. 2013. View Article : Google Scholar : PubMed/NCBI
30	Ribatti D, Nico B, Crivellato E, Roccaro AM and Vacca A: The history of the angiogenic switch concept. Leukemia. 21:44–52. 2007. View Article : Google Scholar : PubMed/NCBI
31	Chen MC, Lee CF, Huang WH and Chou TC: Magnolol suppresses hypoxia-induced angiogenesis via inhibition of HIF-1α/VEGF signaling pathway in human bladder cancer cells. Biochem Pharmacol. 85:1278–1287. 2013.PubMed/NCBI
32	Chen C, Cai S, Wang G, Cao X, Yang X, Luo X, Feng Y and Hu J: c-Myc enhances colon cancer cell-mediated angiogenesis through the regulation of HIF-1α. Biochem Biophys Res Commun. 430:505–511. 2013.PubMed/NCBI
33	Zhou H, Fei W, Bai Y, Zhu S, Luo E, Chen K and Hu J: RNA interference-mediated downregulation of hypoxia-inducible factor-1α inhibits angiogenesis and survival of oral squamous cell carcinoma in vitro and in vivo. Eur J Cancer Prev. 21:289–299. 2012.
34	Jeong JH, Jeong YJ, Cho HJ, et al: Ascochlorin inhibits growth factor-induced HIF-1α activation and tumor-angiogenesis through the suppression of EGFR/ERK/p70S6K signaling pathway in human cervical carcinoma cells. J Cell Biochem. 113:1302–1313. 2012.PubMed/NCBI
35	Chen Y, Gou X, Ke X, Cui H and Chen Z: Human tumor cells induce angiogenesis through positive feedback between CD147 and insulin-like growth factor-I. PLoS One. 7:e409652012. View Article : Google Scholar
36	Tsai AC, Pan SL, Lai CY, et al: The inhibition of angiogenesis and tumor growth by denbinobin is associated with the blocking of insulin-like growth factor-1 receptor signaling. J Nutr Biochem. 22:625–633. 2011. View Article : Google Scholar : PubMed/NCBI
37	Nakamura K, Sasajima J, Mizukami Y, et al: Hedgehog promotes neovascularization in pancreatic cancers by regulating Ang-1 and IGF-1 expression in bone-marrow derived pro-angiogenic cells. PLoS One. 5:e88242010. View Article : Google Scholar
38	Tang X, Zhang Q, Shi S, Yen Y, Li X, Zhang Y, Zhou K and Le AD: Bisphosphonates suppress insulin-like growth factor 1-induced angiogenesis via the HIF-1alpha/VEGF signaling pathways in human breast cancer cells. Int J Cancer. 126:90–103. 2010. View Article : Google Scholar : PubMed/NCBI
39	Shushanov SS, Mar’ina LG, Kravtsova TA, Chernykh YB and Kakpakova ES: Coexpression of two mRNA isoforms of insulin-like growth factor-1 gene and mRNA of YB-1 gene in patients with multiple myeloma. Bull Exp Biol Med. 154:654–657. 2013. View Article : Google Scholar : PubMed/NCBI
40	Baek YY, Cho DH, Choe J, et al: Extracellular taurine induces angiogenesis by activating ERK-, Akt-, and FAK-dependent signal pathways. Eur J Pharmacol. 674:188–199. 2012. View Article : Google Scholar : PubMed/NCBI
41	Chung BH, Cho YL, Kim JD, et al: Promotion of direct angiogenesis in vitro and in vivo by Puerariae flos extract via activation of MEK/ERK-, PI3K/Akt/eNOS-, and Src/FAK-dependent pathways. Phytother Res. 24:934–940. 2010.PubMed/NCBI
42	Shen K, Ji L, Gong C, Ma Y, Yang L, Fan Y, Hou M and Wang Z: Notoginsenoside Ft1 promotes angiogenesis via HIF-1α mediated VEGF secretion and the regulation ofPI3K/AKT and Raf/MEK/ERK signaling pathways. Biochem Pharmacol. 84:784–792. 2012.PubMed/NCBI
43	Zhu C, Qi X, Chen Y, Sun B, Dai Y and Gu Y: PI3K/Akt and MAPK/ERK1/2 signaling pathways are involved in IGF-1-induced VEGF-C upregulation in breast cancer. J Cancer Res Clin Oncol. 137:1587–1594. 2011. View Article : Google Scholar : PubMed/NCBI
44	Yang XM, Wang YS, Zhang J, et al: Role of PI3K/Akt and MEK/ERK in mediating hypoxia-induced expression of HIF-1alpha and VEGF in laser-induced rat choroidal neovascularization. Invest Ophthalmol Vis Sci. 50:1873–1879. 2009. View Article : Google Scholar : PubMed/NCBI
45	Choi IJ, Kim SY, Kwon CH and Kim YK: Rosiglitazone inhibits proliferation of renal proximal tubular cells via down-regulation of ERK and Akt. Ren Fail. 32:103–111. 2010. View Article : Google Scholar : PubMed/NCBI
46	Cantini G, Lombardi A, Piscitelli E, et al: Rosiglitazone inhibits adrenocortical cancer cell proliferation by interfering with the IGF-IR intracellular signaling. PPAR Res. 2008:9040412008. View Article : Google Scholar : PubMed/NCBI