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

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.

Activation of PPARγ suppresses proliferation and induces apoptosis of esophageal cancer cells by inhibiting TLR4-dependent MAPK pathway

“…Previous studies have proposed that activation of PPARγ by RGZ inhibits growth of various types of cancer [20–22]. To verify the inhibitory effect of activation of PPARγ on esophageal cancer cells, EC109 and TE10 cells were treated with 0, 10, 20, and 40 μM of RGZ for 24, 48, and 72 h, and proliferation of EC109 and TE10 cells were determined using MTT assay.…”

Troglitazone inhibits the migration and invasion of PC‑3 human prostate cancer cells by upregulating E‑cadherin and glutathione peroxidase 3

“…Certain previous studies have reported that PPARγ is able to induce anti-proliferative, anti-angiogenic and pro-differentiation signaling pathways in specific tissue types, thus serving a role in the pathogenesis and progression of various types of cancer, including prostate cancer (24,25). Using TZDs as PPARγ ligands, previous studies have investigated the effect of PPARγ on the metastatic potential and investigated its underlying mechanisms (26)(27)(28)(29)(30)(31)(32)(33)(34). TZDs have been demonstrated to be able to suppress cellular migration, invasion and metastasis of cancer in the colon, liver, breast, lung, bladder and prostate gland (26)(27)(28)(29)(30)(31)(32)(33)(34).…”

“…Using TZDs as PPARγ ligands, previous studies have investigated the effect of PPARγ on the metastatic potential and investigated its underlying mechanisms (26)(27)(28)(29)(30)(31)(32)(33)(34). TZDs have been demonstrated to be able to suppress cellular migration, invasion and metastasis of cancer in the colon, liver, breast, lung, bladder and prostate gland (26)(27)(28)(29)(30)(31)(32)(33)(34). For example, in colon cancer, TZD inhibited the development and metastasis of HT-29 human colon cancer cells via its differentiation-promoting effects both in vivo and in vitro by involving the modulation of the E-cadherin/β-catenin system (26).…”

WOMEN IN CANCER THEMATIC REVIEW: New roles for nuclear receptors in prostate cancer

“…Lastly, it has been reported that in prostate cancer tissue, PPARs can promote the upregulation of VEGF thus enhancing tumour vascularisation and growth (Haslmayer et al 2002, Forootan et al 2016. This is quite in conflict with in vitro work and another report which suggests that PPARs inhibit vascularisation (Qin et al 2014), thus further work is needed to elaborate the beneficial or harmful role of PPARs in prostate cancer development and progression.…”

“…PPARs can mediate apoptosis and proliferation as well as prostate cancer cell differentiation (Koeffler 2003, Nagata et al 2008, Wu et al 2016b. PPARs have also been reported to alter prostate cancer motility by regulating the CXCR4/CXCL12 axis (Qin et al 2014). The action of PPAR also has benefit in increasing response to chemotherapy, as treating with PPAR ligands appears to increase apoptosis (Koeffler 2003).…”