| Kinase Assay: |
| Breast Cancer Res Treat. 2012 Nov;136(2):443-55. | | Bergapten induces ER depletion in breast cancer cells through SMAD4-mediated ubiquitination.[Pubmed: 23053665] | ERα function is crucial for the development of normal mammary gland as well as in the process of progression of breast cancer cells. Signals that target receptor levels contribute to regulate estrogens effects in the cells. An intricate cross-regulation has been documented between ERα and TGF-β down-stream molecules: SMAD2, SMAD3, and SMAD4, that can bind ERα and regulate their signaling. Thus, identification of natural anticancer drugs able to influence the latter molecule might provide alternative choices for breast cancer treatment. Taking into account our previous published data we wanted to study the effect of 5-Methoxypsoralen (Bergapten) on ERα and on TGF-β pathway.
METHODS AND RESULTS:
We reported that Bergapten, a coumarin containing compound, effectively depletes ERα in MCF-7 breast cancer sensitive cells and in tamoxifen-resistant clone. The decrease of ERα protein after Bergapten treatment results from the ubiquitine-proteasome pathway as demonstrated by the use of MG-132. IP experiments with ER antibody, demonstrated that the protein has physical interaction with SMAD4 and poly-ubiquitine and the amount of ubiquitinated receptor, linked to SMAD4, is greater under Bergapten. The crucial role played by SMAD4, in this process, emerges from the observation that in breast cancer cells, silencing of SMAD4, resulted in increased expression of endogenous ERα in both control and Bergapten-treated cells, compared to wild- type cells. The same results were confirmed in siRNA TGF-β RII cells.
The results suggest a novel negative regulation of ERα by TGF-β/SMAD4 in breast cancer cells and indicate that the SMAD4 protein is involved in the degradation of ERα induced by Bergapten. CONCLUSIONS:
We propose that Bergapten may efficiently act as a natural antitumoral agent, able to deplete ERα from breast cancer tamoxifen-sensitive and resistant cells, thereby retraining the effect of membrane signals targeting ERα and in such way its mitogenic potentiality. | | FEBS Lett. 2010 Jun 3;584(11):2321-6. | | Breast cancer cell survival signal is affected by bergapten combined with an ultraviolet irradiation.[Pubmed: 20371365] |
METHODS AND RESULTS:
In this study we have reported that Bergapten (B) and Bergapten plus UV (PUVA) are able to significantly affect MCF-7, ZR-75 and SKBR-3 breast cancer cell proliferations. B induced a lowering of PI3K/AKT survival signal in MCF-7 cells even in presence of IGF-I stimulation. Furthermore, B and in a higher extent, PUVA up-regulated the p53 mRNA and the protein content. An increased co-association between p21 WAF and proliferating cell nuclear antigen (PCNA) has been observed in PUVA-treated MCF-7 cells, thus inhibiting DNA replication.
CONCLUSIONS:
These results highlight how B, and its photoactivated compound, exert antiproliferative effects and induce apoptotic responses in breast cancer cells. |
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