Peroxisome proliferator-activated receptor γ ligands inhibit VEGF-mediated vasculogenic mimicry of prostate cancer through the AKT signaling pathway

Qin,Liang; Ren,Ye; Chen,An-Min; Guo,Feng-Jing; Xu,Fei; Gong,Chen; Cheng,Peng; Du,Yu; Liao,Hui

doi:10.3892/mmr.2014.2198

Peroxisome proliferator-activated receptor γ ligands inhibit VEGF-mediated vasculogenic mimicry of prostate cancer through the AKT signaling pathway

Authors:
- Liang Qin
- Ye Ren
- An-Min Chen
- Feng-Jing Guo
- Fei Xu
- Chen Gong
- Peng Cheng
- Yu Du
- Hui Liao
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Affiliations: Department of Orthopedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, P.R. China, Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, P.R. China
Published online on: April 29, 2014 https://doi.org/10.3892/mmr.2014.2198
Pages: 276-282

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Abstract

Vasculogenic mimicry (VM) describes functional vascular channels composed only of tumor cells and its presence predicts a poor prognosis for patients with prostate cancer. The present study demonstrated that prostate cancer PC-3 cells were able to form a patterned matrix or tubular VM in 3D cultures in vitro and rosiglitazone (RSG), the ligand of peroxisome proliferator-activated receptor γ (PPARγ) and effectively inhibited the formation of VM structures in a dose- and PPARγ‑dependent manner. In addition, RSG significantly inhibited prostate cancer cell migration and invasion. The inhibitory effect of RSG on VM formation could be at least partially explained by an RSG-driven downregulation of vascular endothelial growth factor (VEGF) levels and phosphorylation of AKT, which is known to be important in VM. Furthermore, the present study highlighted that VEGF and the phosphoinositide 3-kinase/AKT pathway exert a positive feedback regulation in the process of VM formation. These findings reveal new therapeutic potential for PPARγ ligands in anti‑cancer therapy.

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1	Hanahan D and Folkman J: Patterns and emerging mechanisms of the angiogenic switch during tumorigenesis. Cell. 86:353–364. 1996. View Article : Google Scholar : PubMed/NCBI
2	Döme B, Hendrix MJ, Paku S, Tóvári J and Tímár J: Alternative vascularization mechanisms in cancer: Pathology and therapeutic implications. Am J Pathol. 170:1–15. 2007.PubMed/NCBI
3	Maniotis AJ, Folberg R, Hess A, et al: Vascular channel formation by human melanoma cells in vivo and in vitro: vasculogenic mimicry. Am J Pathol. 155:739–752. 1999. View Article : Google Scholar : PubMed/NCBI
4	Basu GD, Pathangey LB, Tinder TL, Gendler SJ and Mukherjee P: Mechanisms underlying the growth inhibitory effects of the cyclo-oxygenase-2 inhibitor celecoxib in human breast cancer cells. Breast Cancer Res. 7:R422–R435. 2005. View Article : Google Scholar : PubMed/NCBI
5	El Hallani S, Boisselier B, Peglion F, et al: A new alternative mechanism in glioblastoma vascularization: tubular vasculogenic mimicry. Brain. 133:973–982. 2010.PubMed/NCBI
6	Sharma N, Seftor RE, Seftor EA, et al: Prostatic tumor cell plasticity involves cooperative interactions of distinct phenotypic subpopulations: role in vasculogenic mimicry. Prostate. 50:189–201. 2002. View Article : Google Scholar
7	Sun B, Zhang D, Zhang S, Zhang W, Guo H and Zhao X: Hypoxia influences vasculogenic mimicry channel formation and tumor invasion-related protein expression in melanoma. Cancer Lett. 249:188–197. 2007. View Article : Google Scholar : PubMed/NCBI
8	Millimaggi D, Mari M, D’ Ascenzo S, Giusti I, Pavan A and Dolo V: Vasculogenic mimicry of human ovarian cancer cells: role of CD147. Int J Oncol. 35:1423–1428. 2009.PubMed/NCBI
9	Zhang S, Zhang D and Sun B: Vasculogenic mimicry: current status and future prospects. Cancer Lett. 254:157–164. 2007. View Article : Google Scholar : PubMed/NCBI
10	Wang JY, Sun T, Zhao XL, et al: Functional significance of VEGF-a in human ovarian carcinoma: role in vasculogenic mimicry. Cancer Biol Ther. 7:758–766. 2008. View Article : Google Scholar : PubMed/NCBI
11	Liu R, Yang K, Meng C, Zhang Z and Xu Y: Vasculogenic mimicry is a marker of poor prognosis in prostate cancer. Cancer Biol Ther. 13:527–533. 2012. View Article : Google Scholar : PubMed/NCBI
12	Kota BP, Huang TH and Roufogalis BD: An overview on biological mechanisms of PPARs. Pharmacol Res. 51:85–94. 2005. View Article : Google Scholar : PubMed/NCBI
13	Kim S, Lee JJ and Heo DS: PPARgamma ligands induce growth inhibition and apoptosis through p63 and p73 in human ovarian cancer cells. Biochem Biophys Res Commun. 406:389–395. 2011. View Article : Google Scholar : PubMed/NCBI
14	Lyles BE, Akinyeke TO, Moss PE and Stewart LV: Thiazolidinediones regulate expression of cell cycle proteins in human prostate cancer cells via PPARgamma-dependent and PPARgamma-independent pathways. Cell Cycle. 8:268–277. 2009. View Article : Google Scholar
15	Fujita M, Yagami T, Fujio M, et al: Cytotoxicity of troglitazone through PPARgamma-independent pathway and p38 MAPK pathway in renal cell carcinoma. Cancer Lett. 312:219–227. 2011. View Article : Google Scholar : PubMed/NCBI
16	Kim KY, Ahn JH and Cheon HG: Anti-angiogenic action of PPARgamma ligand in human umbilical vein endothelial cells is mediated by PTEN upregulation and VEGFR-2 downregulation. Mol Cell Biochem. 358:375–385. 2011. View Article : Google Scholar : PubMed/NCBI
17	Panigrahy D, Singer S, Shen LQ, et al: PPARgamma ligands inhibit primary tumor growth and metastasis by inhibiting angiogenesis. J Clin Invest. 110:923–932. 2002. View Article : Google Scholar : PubMed/NCBI
18	Tian L, Zhou J, Casimiro MC, et al: Activating peroxisome proliferator-activated receptor gamma mutant promotes tumor growth in vivo by enhancing angiogenesis. Cancer Res. 69:9236–9244. 2009. View Article : Google Scholar : PubMed/NCBI
19	Lissitzky JC, Parriaux D, Ristorcelli E, Verine A, Lombardo D and Verrando P: Cyclic AMP signaling as a mediator of vasculogenic mimicry in aggressive human melanoma cells in vitro. Cancer Res. 69:802–809. 2009. View Article : Google Scholar : PubMed/NCBI
20	Liu H, Chen A, Guo F and Yuan L: A short-hairpin RNA targeting osteopontin downregulates MMP-2 and MMP-9 expressions in prostate cancer PC-3 cells. Cancer Lett. 295:27–37. 2010. View Article : Google Scholar : PubMed/NCBI
21	Yamashita D, Shimizu M and Osumi T: Mechanism for the action of PPARs. Nihon Rinsho. 63:536–537. 2005.(In Japanese).
22	Shukla S, Maclennan GT, Hartman DJ, Fu P, Resnick MI and Gupta S: Activation of PI3K-Akt signaling pathway promotes prostate cancer cell invasion. Int J Cancer. 121:1424–1432. 2007. View Article : Google Scholar : PubMed/NCBI
23	Wang J, Wang J, Sun Y, Song W, Nor JE, Wang CY and Taichman RS: Diverse signaling pathways through the SDF-1/CXCR4 chemokine axis in prostate cancer cell lines leads to altered patterns of cytokine secretion and angiogenesis. Cell Signal. 17:1578–1592. 2005. View Article : Google Scholar : PubMed/NCBI
24	Jemal A, Bray F, Center MM, Ferlay J, Ward E and Forman D: Global cancer statistics. CA Cancer J Clin. 61:69–90. 2011. View Article : Google Scholar
25	de Bono JS, Oudard S, Ozguroglu M, et al: Prednisone plus cabazitaxel or mitoxantrone for metastatic castration-resistant prostate cancer progressing after docetaxel treatment: a randomised open-label trial. Lancet. 376:1147–1154. 2010.
26	Samaranayake H, Määttä AM, Pikkarainen J and Ylä-Herttuala S: Future prospects and challenges of antiangiogenic cancer gene therapy. Hum Gene Ther. 21:381–396. 2010. View Article : Google Scholar : PubMed/NCBI
27	van der Schaft DW, Seftor RE, Seftor EA, et al: Effects of angiogenesis inhibitors on vascular network formation by human endothelial and melanoma cells. J Natl Cancer Inst. 96:1473–1477. 2004.PubMed/NCBI
28	Pàez-Ribes M, Allen E, Hudock J, et al: Antiangiogenic therapy elicits malignant progression of tumors to increased local invasion and distant metastasis. Cancer Cell. 15:220–231. 2009.PubMed/NCBI
29	Qu B, Guo L, Ma J and Lv Y: Antiangiogenesis therapy might have the unintended effect of promoting tumor metastasis by increasing an alternative circulatory system. Med Hypotheses. 74:360–361. 2010. View Article : Google Scholar : PubMed/NCBI
30	Xu Y, Li Q, Li XY, Yang QY, Xu WW and Liu GL: Short-term anti-vascular endothelial growth factor treatment elicits vasculogenic mimicry formation of tumors to accelerate metastasis. J Exp Clin Cancer Res. 31:162012. View Article : Google Scholar : PubMed/NCBI
31	Itzhaki O, Greenberg E, Shalmon B, et al: Nicotinamide inhibits vasculogenic mimicry, an alternative vascularization pathway observed in highly aggressive melanoma. PLoS One. 8:e571602013. View Article : Google Scholar
32	Fan YZ and Sun W: Molecular regulation of vasculogenic mimicry in tumors and potential tumor-target therapy. World J Gastrointest Surg. 2:117–127. 2010. View Article : Google Scholar : PubMed/NCBI
33	Goetze S, Eilers F, Bungenstock A, et al: PPAR activators inhibit endothelial cell migration by targeting Akt. Biochem Biophys Res Commun. 293:1431–1437. 2002. View Article : Google Scholar : PubMed/NCBI
34	Vartanian A, Stepanova E, Grigorieva I, Solomko E, Baryshnikov A and Lichinitser M: VEGFR1 and PKCalpha signaling control melanoma vasculogenic mimicry in a VEGFR2 kinase-independent manner. Melanoma Res. 21:91–98. 2011. View Article : Google Scholar : PubMed/NCBI
35	van der Schaft DW, Hillen F, Pauwels P, et al: Tumor cell plasticity in Ewing sarcoma, an alternative circulatory system stimulated by hypoxia. Cancer Res. 65:11520–11528. 2005.PubMed/NCBI
36	Lirdprapamongkol K, Chiablaem K, Sila-Asna M, Surarit R, Bunyaratvej A and Svasti J: Exploring stemness gene expression and vasculogenic mimicry capacity in well- and poorly-differentiated hepatocellular carcinoma cell lines. Biochem Biophys Res Commun. 422:429–435. 2012. View Article : Google Scholar
37	Yoshizaki T, Motomura W, Tanno S, Kumei S, Yoshizaki Y and Okumura T: Thiazolidinediones enhance vascular endothelial growth factor expression and induce cell growth inhibition in non-small-cell lung cancer cells. J Exp Clin Cancer Res. 29:222010. View Article : Google Scholar
38	Hess AR, Seftor EA, Seftor RE and Hendrix MJ: Phosphoinositide 3-kinase regulates membrane Type 1-matrix metalloproteinase (MMP) and MMP-2 activity during melanoma cell vasculogenic mimicry. Cancer Res. 63:4757–4762. 2003.PubMed/NCBI
39	Chetty C, Lakka SS, Bhoopathi P and Rao JS: MMP-2 alters VEGF expression via alphaVbeta3 integrin-mediated PI3K/AKT signaling in A549 lung cancer cells. Int J Cancer. 127:1081–1095. 2010. View Article : Google Scholar : PubMed/NCBI
40	Chen WC, Lin MS and Bai X: Induction of apoptosis in colorectal cancer cells by peroxisome proliferators-activated receptor gamma activation up-regulating PTEN and inhibiting PI3K activity. Chin Med J (Engl). 118:1477–1481. 2005.PubMed/NCBI
41	Trisciuoglio D, Iervolino A, Zupi G and Del Bufalo D: Involvement of PI3K and MAPK signaling in bcl-2-induced vascular endothelial growth factor expression in melanoma cells. Mol Biol Cell. 16:4153–4162. 2005. View Article : Google Scholar : PubMed/NCBI
42	Pore N, Gupta AK, Cerniglia GJ and Maity A: HIV protease inhibitors decrease VEGF/HIF-1alpha expression and angiogenesis in glioblastoma cells. Neoplasia. 8:889–895. 2006. View Article : Google Scholar : PubMed/NCBI
43	Zhong H, Chiles K, Feldser D, et al: Modulation of hypoxia-inducible factor 1alpha expression by the epidermal growth factor/phosphatidylinositol 3-kinase/PTEN/AKT/FRAP pathway in human prostate cancer cells: implications for tumor angiogenesis and therapeutics. Cancer Res. 60:1541–1545. 2000.