3,6-dihydroxyflavone suppresses the epithelial-mesenchymal transition in breast cancer cells by inhibiting the Notch signaling pathway

Abstract

The epithelial to mesenchymal transition (EMT) is a critical developmental program in cancer stem cell (CSC) maintenance and in cancer metastasis. Here, our study found that 3,6-DHF could effectively inhibit EMT in BC cells in vitro and in vivo. 3,6-DHF effectively inhibits the formation and proliferation of BCSCs, and consequently reduces the tumor-initiating capacity of tumor cells in NOD/SCID mice. Optical in vivo imaging of cancer metastasis showed that 3,6-DHF administration suppresses the lung metastasis of BC cells in vivo. Further studies indicated that 3,6-DHF down-regulates Notch1, NICD, Hes-1 and c-Myc, consequently decreasing the formation of the functional transcriptional unit of NICD-CSL-MAML, causing Notch signaling inactivation in BC cells. Over-expression of Notch1 or inhibition of miR-34a significantly reduced the inhibitory effects of 3,6-DHF on EMT, CSCs, as well as cells migration and invasion in BC cells. These data indicated that 3,6-DHF effectively inhibits EMT and CSCs, as well as cells migration and invasion in BC cells, in which miR-34a-mediated Notch1 down-regulation plays a crucial role.

Small molecule inhibitors of epithelial‐mesenchymal transition for the treatment of cancer and fibrosis

“…67,185,186 3,6-Dihydroxyflavone is ubiquitous in vegetables and fruits and blocks EMT in breast cancer cells through suppressing the Notch signaling pathway. 47 Moreover, luteolin inhibited EMT in gastric cancer by the Notch signaling pathway. 38 In addition, emodin is a main bioactive component of Polygonum cuspidatum that suppressed EMT in alveolar epithelial cells via the Notch signaling pathway.…”

“…Another γ‐secretase inhibitor, RO4929097, not only inhibited EMT, invasion, and metastasis in cervical cancer HeLa and CaSki cells but also exerted significant therapeutic effects in patients with recurrent malignant glioma, cervical and colon cancer and advanced solid tumors in clinical trials . 3,6‐Dihydroxyflavone is ubiquitous in vegetables and fruits and blocks EMT in breast cancer cells through suppressing the Notch signaling pathway . Moreover, luteolin inhibited EMT in gastric cancer by the Notch signaling pathway .…”

CLDN-1 promoted the epithelial to migration and mesenchymal transition (EMT) in human bronchial epithelial cells via Notch pathway

“…Notch signaling is activated by NICD, followed by the NICD cleavage products translocating to the nucleus and activating the expression of the primary Notch target gene Hes-1 [19,20]. In order to explore whether the Notch signaling pathway participated in the effect of siCLDN-1 on the regulation of migration and EMT, we determined the effects of siCLDN-1 on NICD and Hes-1 expression.…”

Recent progress on the effects of microRNAs and natural products on tumor epithelial–mesenchymal transition

“…As a result, tumor invasion, migration, and stem cell formation were inhibited. Further studies showed that Notch1 inhibition and miR-34a upregulation were involved 116. Nevertheless, in tamoxifen-resistant MCF-7TR breast cancer cells, resveratrol reversed EMT by reducing endogenous TGF-β and inhibiting SMAD phosphorylation 117…”