VSP‑17 suppresses the migration and invasion of triple‑negative breast cancer cells through inhibition of the EMT process via the PPARγ/AMPK signaling pathway

Abstract

VSP-17, a novel peroxisome proliferator-activated receptor γ (PPARγ) agonist, has been previously demonstrated to suppress the metastasis of triple-negative breast cancer (TNBC) by upregulating the expression levels of E-cadherin, which is a key marker of epithelial-mesenchymal transition (EMT). However, the mechanism of action of VSP-17, in particular whether it may be associated with the EMT process, remains unknown. The present study investigated the ability of VSP-17 to inhibit the invasiveness and migratory ability of TNBC cell lines (MDA-MB-231 and MDA-MB-453) performed in in vitro experiments. including cell migration assay, cell invasion assay, cell transfection, RT-qPCR, western blot (WB) analysis and immunofluorescence. The present study aimed to ascertain whether and how the PPARγ/AMP-activated protein kinase (AMPK) signaling pathway serves a role in the inhibitory effects of VSP-17 on cell migration and invasion. The results revealed that both treatment with compound C (an AMPK inhibitor) and transfection with small interfering RNA (si)AMPK notably diminished the inhibitory effect of VSP-17 treatment on the migration and invasion of MDA-MB-231 and MDA-MB-453 cells, indicating that VSP-17 may, at least partly, exert its effects via AMPK. Furthermore, both compound C and siAMPK markedly diminished the VSP-17-induced downregulation of vimentin expression levels and upregulation of E-cadherin expression levels, further indicating that the VSP-17-induced inhibition of the EMT process may be dependent on AMPK. The combination of GW9662 (a PPARγ antagonist) or siPPARγ diminished the inhibitory effect of VSP-17 treatment on the migration and invasion of the TNBC cells, indicating that PPARγ may serve an important role in the VSP-17-induced inhibition of the migration and invasion of TNBC cells. In addition, both GW9662 and siPPARγ significantly reversed the VSP-17-induced downregulation of vimentin expression levels and upregulation of E-cadherin expression levels, implying that the VSP-17-induced inhibition of the EMT process may be dependent on PPARγ. VSP-17 treatment also upregulated the expression levels of p-AMPK, which could be reversed by either GW9662 or siPPARγ, indicating that the VSP-17-induced activation of the AMPK signaling pathway was PPARγ-dependent. In conclusion, the findings of the present study indicated that VSP-17 treatment may inhibit the migration and invasion of TNBC cells by suppressing the EMT process via the PPARγ/AMPK signaling pathway.

PPARG: A Promising Therapeutic Target in Breast Cancer and Regulation by Natural Drugs

“…Recent findings suggest that PPARG can affect a variety of biological functions by regulating and expressing different signaling pathways, such as β 2-adrenaline promoting of BC growth and angiogenesis through the downregulation of PPARG [ 51 ], and as a PPAR γ agonist, VSP-17 is capable of inhibiting the process of EMT, thereby suppressing the migration and invasion of triple-negative BC cells, through the PPARG/AMPK signaling pathway [ 52 ]. Correlation analysis of PPARG with pathways reveals that PPARG is highly correlated with angiogenesis, apoptosis, EMT markers, fatty acid biosynthesis, fatty acid degradation, glycolysis–gluconeogenesis, and other pathways.…”

Asiaticoside hampers epithelial–mesenchymal transition by promoting PPARG expression and suppressing P2RX7‐mediated TGF‐β/Smad signaling in triple‐negative breast cancer

“…Consistently, VSP‐17, a PPARG agonist, suppressed the liver metastasis of TNBC by enhancing the expression of E‐cadherin (Y. Wang et al, 2018). Furthermore, GW9662 (a PPARG antagonist) or siRNA targeting PPARG counteracted the repressive effect of VSP‐17 treatment on the migration and invasion of the TNBC cells and reversed the VSP‐17‐induced vimentin downregulation and E‐cadherin upregulation (Xu et al, 2021). Likewise, in the present study, shRNA targeting PPARG could perturb the antitumor effects of AC, resulting in the restoration of TNBC cell migration and invasion, the acquirement of vimentin expression, and the loss of E‐cadherin and ZO‐1.…”

The epithelial–mesenchymal plasticity landscape: principles of design and mechanisms of regulation

“…Following this trend, fatty acids in mesenchymal-like cells are on average shorter 282 , and more unsaturated 282,298 . Lastly, aberrant synthesis of lipid signalling molecules can activate downstream signalling cascades; for example, the PPAR transcription factor family, activated by fatty acid ligands, inhibits EMT both in cancer cells [299][300][301][302] and in fibrosis [303][304][305][306][307] . Furthermore, eicosanoids regulate EMP; whereas prostaglandin E2 promotes EMT [308][309][310][311][312] , lipoxin A4 inhibits type 1 313 , type 2 [314][315][316] and type 3 317,318 EMT.…”