Baicalein inhibits fibronectin-induced epithelial–mesenchymal transition by decreasing activation and upregulation of calpain-2

Abstract

The extracellular matrix protein fibronectin (FN) facilitates tumorigenesis and the development of breast cancer. Inhibition of the FN-induced cellular response is a potential strategy for breast cancer treatment. In the present study, we investigated the effects of the flavonoid baicalein on FN-induced epithelial–mesenchymal transition (EMT) in MCF-10A breast epithelial cells and in a transgenic mouse MMTV-polyoma middle T antigen breast cancer model (MMTV-PyMT). Baicalein inhibited FN-induced migration, invasion, and F-actin remodeling. Baicalein also suppressed FN-induced downregulation of the epithelial markers E-cadherin and ZO-1 and upregulation of the mesenchymal markers N-cadherin, vimentin, and Snail. Further investigation revealed that calpain-2 was involved in baicalein suppression of FN-induced EMT. Baicalein significantly decreased FN-enhanced calpain-2 expression and activation by suppressing its plasma membrane localization, substrate cleavage, and degradation of its endogenous inhibitor calpastatin. Overexpression of calpain-2 in MCF-10A cells by gene transfection partially blocked the inhibitory effect of baicalein on FN-induced EMT changes. In addition, baicalein inhibited calpain-2 by decreasing FN-increased intracellular calcium ion levels and extracellular signal-regulated protein kinases activation. Baicalein significantly decreased tumor onset, growth, and pulmonary metastasis in a spontaneous breast cancer MMTV-PyMT mouse model. Baicalein also reduced the expression of FN, calpain-2, and vimentin, but increased E-cadherin expression in MMTV-PyMT mouse tumors. Overall, these results revealed that baicalein markedly inhibited FN-induced EMT by inhibiting calpain-2, thus providing novel insights into the pharmacological action and mechanism of baicalein. Baicalein may therefore possess therapeutic potential for the treatment of breast cancer though interfering with extracellular matrix–cancer cell interactions.

Baicalein restrains proliferation, migration, and invasion of human malignant melanoma cells by down-regulating colon cancer associated transcript-1

“…One of the ingredients is baicalein (BAI), which is commonly regarded as useful adjuvant therapeutic pharmaceutical for various diseases (6). Thus far, a number of researchers tested the efficacy of BAI on malignant tumors, such as breast carcinoma (7), non-small-cell lung carcinoma (8), cervical carcinoma (9), and carcinoma of urinary bladder (10). Moreover, previous research indicated that BAI impeded cell proliferation and melanogenesis of B16F10 mouse melanoma cells (11,12).…”

Baicalein inhibits FURIN‐MT1‐MMP‐mediated invasion of ectopic endometrial stromal cells in endometriosis possibly by reducing the secretion of TGFB1

“…In particular, studies have shown that baicalein inhibits the invasion of cancer cells by inhibiting EMT through upregulating of calpain-2, inactivating the PI3K/Akt signaling pathway in B16F10 mouse melanoma cells, and suppressing 17B-estradiolinduced invasion via the G protein-coupled receptor 30 signaling pathway. [44][45][46] Herein, we demonstrated that baicalein reduced the F I G U R E 4 Baicalein suppresses FURIN and act-MT1-MMP by inhibiting the secretion of TGFB1 from EcESCs via the Smad3 pathway. A, ELISA was used to detect the levels of TGFB1 following treatment with baicalein for 48 h (n = 10).…”

The Adipose Microenvironment Dysregulates the Mammary Myoepithelial Cells and Could Participate to the Progression of Breast Cancer

“…On the contrary, Fibronectin (FN), a key component of the tumor ECM, seems to facilitate tumor formation, proliferation and angiogenesis. Its expression in breast tissue was positively correlated with an invasive and metastatic phenotype and negatively associated with survival and clinical outcome in breast cancer patients ( Chen et al, 2019 ). Thus these two genes could constitute privileged targets for the action of adipose cells leading to the loss of MEC function.…”