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

Abstract

Triple-negative breast cancer (TNBC) accounts for 10-20% of all human ductal adenocarcinomas and has a poor prognosis relative to other subtypes because of its high propensity to develop metastases. Here, the anticancer effects of asiaticoside (AC) against TNBC and the possible underlying mechanism were examined. We found that AC inhibited the TGF-β1 expression and the SMAD2/3 phosphorylation in TNBC cells, thereby impairing the TGF-β/SMAD signaling. AC inhibited the migration, invasion, and epithelial-mesenchymal transition (EMT) of TNBC cells by suppressing the TGF-β/SMAD signaling. Meanwhile, AC inhibited the lung metastasis of TNBC cells in vivo and the expression of p-SMAD2/3 and vimentin, and increased the expression of E-cadherin and ZO-1 in the lung. Peroxisome proliferator activated receptor gamma (PPARG) was identified as a potential target of AC. AC increased PPARG expression, while PPARG knockdown attenuated the therapeutic effect of AC. AC-mediated PPARG overexpression suppressed the transcription of P2X purinoceptor 7 (P2RX7). The restoration of P2RX7 reversed the therapeutic effect of AC. These results suggested that AC blocked P2RX7-mediated TGF-β/SMAD signaling by increasing PPARG expression, thereby suppressing EMT in TNBC.

The P2X7 Receptor in Oncogenesis and Metastatic Dissemination: New Insights on Vesicular Release and Adenosinergic Crosstalk

“…EMT is a process of cell transdifferentiation originally adopted during embryogenesis and co-opted during metastasis, causing an increase in cancer cell migration linked to loss of cell polarity and down-regulation of adhesion molecules [99]. This mechanism was confirmed as the basis of P2X7-mediated invasiveness in recent publications covering the negative prognostic role of the receptor in oncological conditions as different as neuroblastoma [44], triple-negative breast cancer [100] and muscle-invasive bladder carcinoma [101]. In addition to EMT, metastasis is favored by signaling pathways and mechanisms implicated in tissue regeneration, wound healing, and adaptation to stress [90] that have been associated with P2X7 activity both in cancer and other physio-pathological conditions [17,53,55,84,96,[102][103][104][105][106][107][108].…”

SMAD Proteins in TGF-β Signalling Pathway in Cancer: Regulatory Mechanisms and Clinical Applications

“…At the same time, SMAD proteins were found to act as targets for a variety of breast cancer drugs. In triple negative breast cancer, Asiaticoside inhibited the expression of TGF-β1 and phosphorylation of SMAD2/3, suppressing the development of triple negative breast cancer [117]. Trx-SARA is an example of a peptide aptamer that links to SMAD2 and SMAD3, disrupting their communication with SMAD4.…”