Sanguisorba officinalis L. Suppresses Triple-Negative Breast Cancer Metastasis by Inhibiting Late-Phase Autophagy via Hif-1α/Caveolin-1 Signaling

Abstract

Sanguisorba officinalis L. (SA) is a common herb for cancer treatment in the clinic, particularly during the consolidation phase to prevent occurrence or metastasis. Nevertheless, there are limited studies reporting the molecular mechanisms about its anti-metastatic function. It is well demonstrated that autophagy is one of the critical mechanisms accounting for metastasis and anti-cancer pharmacological actions of Chinese herbs. On the threshold, the regulatory effects and molecular mechanisms of SA in suppressing autophagy-related breast cancer metastasis were investigated in this study. In vitro findings demonstrated that SA potently suppressed the proliferation, colony formations well as metastasis process in triple-negative breast cancer. Network and biological analyses predicted that SA mainly targeted caveolin-1 (Cav-1) to induce anti-metastatic effects, and one of the core mechanisms was via regulation of autophagy. Further experiments—including western blotting, transmission electron microscopy, GFP-mRFP-LC3 immunofluorescence, and lysosomal-activity detection—validated SA as a potent late-stage autophagic inhibitor by increasing microtubule-associated light chain 3-II (LC3-II) conversion, decreasing acidic vesicular-organelle formation, and inducing lysosomal dysfunction even under conditions of either starvation or hypoxia. Furthermore, the anti-autophagic and anti-metastatic activity of SA was Cav-1-dependent. Specifically, Cav-1 knockdown significantly facilitated SA-mediated inhibition of autophagy and metastasis. Furthermore, hypoxia inducible factor-1α (Hif-1α) overexpression attenuated the SA-induced inhibitory activities on Cav-1, autophagy, and metastasis, indicating that SA may have inhibited autophagy-related metastasis via Hif-1α/Cav-1 signaling. In both mouse breast cancer xenograft and zebrafish xenotransplantation models, SA inhibited breast cancer growth and inhibited late-phase autophagy in vivo, which was accompanied by suppression of Hif-1α/Cav-1 signaling and the epithelial-mesenchymal transition. Overall, our findings not only indicate that SA acts as a novel late-phase autophagic inhibitor with anti-metastatic activities in triple-negative breast cancer, but also highlight Cav-1 as a regulator in controlling late-phase autophagic activity.

MiR-27a-3p promotes the osteogenic differentiation by activating CRY2/ERK1/2 axis

“…In present study, (Zheng et al 2020 ; Zhou et al 2020 ) we found that CRY2 knockdown or honokil reversed the effect of miR-27a-3p inhibitor on osteogenic differentiation via regulating apoptosis and autophagy. Furthermore, co-transfection of (Wang et al 2020 ) miR-27a-3p inhibitor and CRY2 shRNA or honokil induced cell autophagy via mediation of LC3.…”

“…Dong Y et al found that miR-27a-3p could regulate the autophagy in LPS-treated HUVECs through targeting SLIT2 (Dong et al 2020 ; Xie et al 2020 ). LC3 was considered to play regulatory roles in autophagy (Wang et al 2020 ). In present study, (Zheng et al 2020 ; Zhou et al 2020 ) we found that CRY2 knockdown or honokil reversed the effect of miR-27a-3p inhibitor on osteogenic differentiation via regulating apoptosis and autophagy.…”

Insights Into the Function and Clinical Application of HDAC5 in Cancer Management

“…During EMT, epithelial cells lose their polarity and acquire mesenchymal-like features along with the capacity to migrate and invade other tissues ( 108 ). An increasing number of studies have reported that the change in the oxygen level in cancer microenvironments and the HIF1α-induced hypoxia signal transduction pathway acted as a vital regulator of EMT, which played a key role in hypoxia-induced cancer invasion and metastasis ( 109 , 110 ).…”

Sanguisorbae Radix Suppresses Colorectal Tumor Growth Through PD-1/PD-L1 Blockade and Synergistic Effect With Pembrolizumab in a Humanized PD-L1-Expressing Colorectal Cancer Mouse Model

“…Although several reports have shown SRE use in treatment of human CRC, breast cancer, and prostate cancer ( 18 , 24 , 25 ), SRE’s anticancer activities via mediation of T cells had not been defined. This study demonstrated the experimental evidence on antitumor immunity by improving T cell activity with SRE.…”