Peroxisome proliferator‑activated receptor γ agonist rosiglitazone inhibits migration and invasion of prostate cancer cells through inhibition of the CXCR4/CXCL12 axis

Qin,Liang; Gong,Chen; Chen,An‑Min; Guo,Feng‑Jing; Xu,Fei; Ren,Ye; Liao,Hui

doi:10.3892/mmr.2014.2232

Peroxisome proliferator‑activated receptor γ agonist rosiglitazone inhibits migration and invasion of prostate cancer cells through inhibition of the CXCR4/CXCL12 axis

Authors:
- Liang Qin
- Chen Gong
- An‑Min Chen
- Feng‑Jing Guo
- Fei Xu
- Ye Ren
- 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: May 13, 2014 https://doi.org/10.3892/mmr.2014.2232
Pages: 695-700

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Abstract

It has been indicated that the C‑X‑C chemokine receptor type 4/C‑X‑C chemokine ligand 12 (CXCR4/CXCL12) axis is involved in promoting invasion and metastasis in tumors. Therefore, novel drugs capable of downregulating the CXCR4/CXCL12 axis may demonstrate potential for the treatment of metastatic prostate cancer (PCa). Rosiglitazone (RSG), a thiazolidinedione ligand of the peroxisome proliferator‑activated receptor (PPAR) γ, has been found to inhibit proliferation, induce apoptosis, suppress angiogenesis and inhibit metastasis. However, the precise mechanisms by which RSG regulates CXCR4 gene expression and the consequent effects on prostate cell migration and invasion are not fully understood. In this study, it was observed that RSG is capable of downregulating the expression of CXCR4 in PCa cells in a dose‑, time‑ and PPARγ‑dependent manner. Furthermore, it was observed that the downregulation of CXCR4 expression occurred at a transcriptional level, as indicated by a reduction in CXCR4 mRNA expression. Suppression of CXCR4 expression by RSG further correlated with the inhibition of CXCL12‑induced migration and invasion in PCa cells. Analysis of the predominant intracellular signaling pathways that act downstream of the activated CXCR4/CXCL12 axis, namely the phosphatidyl inositol 3‑kinase (PI3K)‑protein kinase B (Akt) cascades, revealed that RSG rapidly interferes with the phosphorylation/activation of Akt, which mediates CXCL12‑stimulated migration and invasion. Overall, the findings of this study suggest that RSG represents a novel inhibitor of CXCR4 expression and, thus, has significant potential as a powerful therapeutic agent for the treatment of metastatic PCa.

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1	Jemal A, Siegel R, Ward E, Hao Y, Xu J and Thun MJ: Cancer statistics, 2009. CA Cancer J Clin. 59:225–249. 2009. View Article : Google Scholar
2	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
3	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
4	Zhou J, Zhang W, Liang B, et al: PPARgamma activation induces autophagy in breast cancer cells. Int J Biochem Cell Biol. 41:2334–2342. 2009. View Article : Google Scholar : PubMed/NCBI
5	Kim S, Lee JJ and Heo DS: PPARγ ligands induce growth inhibition and apoptosis through p63 and p73 in human ovarian cancer cells. Biochem Biophys Res Commun. 406:389–395. 2011.
6	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
7	Shen D, Deng C and Zhang M: Peroxisome proliferator-activated receptor gamma agonists inhibit the proliferation and invasion of human colon cancer cells. Postgrad Med J. 83:414–419. 2007. View Article : Google Scholar : PubMed/NCBI
8	Jan HJ, Lee CC, Lin YM, Lai JH, Wei HW and Lee HM: Rosiglitazone reduces cell invasiveness by inducing MKP-1 in human U87MG glioma cells. Cancer Lett. 277:141–148. 2009. View Article : Google Scholar : PubMed/NCBI
9	Fujita M, Yagami T, Fujio M, et al: Cytotoxicity of troglitazone through PPARγ-independent pathway and p38 MAPK pathway in renal cell carcinoma. Cancer Lett. 312:219–227. 2011.
10	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
11	Zhang K, Chen D, Jiao X, et al: Slug enhances invasion ability of pancreatic cancer cells through upregulation of matrix metalloproteinase-9 and actin cytoskeleton remodeling. Lab Invest. 91:426–438. 2011. View Article : Google Scholar
12	Shanmugam MK, Manu KA, Ong TH, et al: Inhibition of CXCR4/CXCL12 signaling axis by ursolic acid leads to suppression of metastasis in transgenic adenocarcinoma of mouse prostate model. Int J Cancer. 129:1552–1563. 2011. View Article : Google Scholar : PubMed/NCBI
13	Yamashita D, Shimizu M and Osumi T: Mechanism for the action of PPARs. Nihon Rinsho. 63:536–537. 2005.(In Japanese).
14	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
15	Han S and Roman J: Rosiglitazone suppresses human lung carcinoma cell growth through PPARgamma-dependent and PPARgamma-independent signal pathways. Mol Cancer Ther. 5:430–437. 2006. View Article : Google Scholar : PubMed/NCBI
16	Richard CL and Blay J: Thiazolidinedione drugs down-regulate CXCR4 expression on human colorectal cancer cells in a peroxisome proliferator activated receptor gamma-dependent manner. Int J Oncol. 30:1215–1222. 2007.
17	Yoshizumi T, Ohta T, Ninomiya I, et al: Thiazolidinedione, a peroxisome proliferator-activated receptor-gamma ligand, inhibits growth and metastasis of HT-29 human colon cancer cells through differentiation-promoting effects. Int J Oncol. 25:631–639. 2004.
18	Kulke MH, Demetri GD, Sharpless NE, et al: A phase II study of troglitazone, an activator of the PPARgamma receptor, in patients with chemotherapy-resistant metastatic colorectal cancer. Cancer J. 8:395–399. 2002. View Article : Google Scholar : PubMed/NCBI
19	Darash-Yahana M, Pikarsky E, Abramovitch R, et al: Role of high expression levels of CXCR4 in tumor growth, vascularization, and metastasis. FASEB J. 18:1240–1242. 2004.PubMed/NCBI
20	Arya M, Patel HR, McGurk C, et al: The importance of the CXCL12-CXCR4 chemokine ligand-receptor interaction in prostate cancer metastasis. J Exp Ther Oncol. 4:291–303. 2004.PubMed/NCBI
21	Xing Y, Liu M, Du Y, et al: Tumor cell-specific blockade of CXCR4/SDF-1 interactions in prostate cancer cells by hTERT promoter induced CXCR4 knockdown: A possible metastasis preventing and minimizing approach. Cancer Biol Ther. 7:1839–1848. 2008. View Article : Google Scholar : PubMed/NCBI
22	Kreisberg JI, Malik SN, Prihoda TJ, et al: Phosphorylation of Akt (Ser473) is an excellent predictor of poor clinical outcome in prostate cancer. Cancer Res. 64:5232–5236. 2004. View Article : Google Scholar : PubMed/NCBI
23	Ayala G, Thompson T, Yang G, et al: High levels of phosphorylated form of Akt-1 in prostate cancer and non-neoplastic prostate tissues are strong predictors of biochemical recurrence. Clin Cancer Res. 10:6572–6578. 2004. View Article : Google Scholar : PubMed/NCBI
24	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
25	Chinni SR, Sivalogan S, Dong Z, et al: CXCL12/CXCR4 signaling activates Akt-1 and MMP-9 expression in prostate cancer cells: the role of bone microenvironment-associated CXCL12. Prostate. 66:32–48. 2006. View Article : Google Scholar : PubMed/NCBI
26	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
27	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
28	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