Baicalein Inhibits Epithelial to Mesenchymal Transition via Downregulation of Cyr61 and LOXL-2 in MDA-MB231 Breast Cancer Cells

Abstract

Epithelial-mesenchymal transition (EMT) is a critical step in the acquisition of the migratory and invasive capabilities associated with metastatic competence. Cysteine-rich protein 61 (CCN1/Cyr61) has been implicated as an important mediator in the proliferation and metastasis of breast cancer. Hence, Cyr61 and associated pathways are attractive targets for therapeutic interventions directed against the EMT. In the present study, we report that baicalein significantly inhibits the expression of Cyr61 and migration and invasion of MDA-MB231 human breast cancer cells. Exposure to baicalein led to increased E-cadherin expression, possibly due to the ubiquitination of Snail and Slug, which was mediated by the Cyr61/Akt/glycogen synthase kinase 3β (GSK3β) pathway. Further analysis revealed that baicalein inhibited the expression of lysyl oxidase like-2 (LOXL-2), which is a functional collaborator of Snail and Slug, and subsequently attenuated the direct interaction between LOXL-2 and Snail or Slug, thereby enhancing GSK3β-dependent Snail and Slug degradation. Our findings provide new insights into the antimetastatic mechanism of baicalein and may contribute to its beneficial use in breast cancer therapies.

Lysyl Oxidase–like Protein LOXL2 Promotes Lung Metastasis of Breast Cancer

“…No changes in Snail1 mRNA level were detected in PyMT cells irrespective of their Loxl2 status (Fig. 6C) suggesting that Loxl2 could promote Snail1 stability in PyMT cells, as previously reported in other cell systems (23, 40, 41). Importantly, nuclear Snail1 staining was significantly decreased in primary PyMT;L2 Δ/- KO tumors compared to their controls (Fig.…”

“…This fact, together with the proposed Loxl2 involvement in EMT and Snail1 stabilization (23, 40, 41) and in tumor cell stemness (52), provides additional Loxl2-dependent mechanisms, not necessarily linked to its enzymatic activity (25), to control tumor progression. The ability of LOXL2 to negatively regulate tumor differentiation in vivo has been demonstrated in squamous cell carcinoma (22).…”

KRas-ERK signalling promotes the onset and maintenance of uveal melanoma through regulating JMJD6-mediated H2A.X phosphorylation at tyrosine 39

“…CYR61 is a connective tissue growth factor which has been considered as a crucial mediator in the developing and metastasis of cancers [26]. High expression of CYR61 was present in cervical cancer [27] and oesophageal squamous cell carcinoma [28], and exerted diverse functions in several types of cancers [29].…”

Structural Insight into the In Vitro Anti-Intravasative Properties of Flavonoids

“…Similar to the flavonoids above, oroxylin A, wogonin, and baicalein were also reported to inhibit EMT marker expression in MCF-7, A549, and MDA-MB231 cell lines, respectively [53][54][55] and to inhibit MMP2/9, migration and invasiveness of MDA-MB231 cells [56][57][58]. In a xenograft nude mouse model, baicalein inhibited tumor metastasis [59].…”