Curcumol inhibits breast cancer growth via NCL/ERα36 and the PI3K/AKT pathway

Background: Breast cancer (BC) is the most common malignancy worldwide. ER alpha 36 (ER alpha 66 variant) is expressed in many breast cancer cells, especially highly expressed in tamoxifen (TAM)-resistant cell lines and triple-negative breast cancer, and our previous work revealed that nucleolin (NCL) is a protein target of curcumol. This study is aimed at investigating the effect and mechanism of curcumol on ER alpha 36 positive breast cancer cells, and the relationship between curcumol's target protein NCL and ER alpha 36. Study design: Application of in vivo and in vitro studies to reveal the mechanism of curcumol in inhibiting BC growth and the relationship between curcumol's target protein NCL and ER alpha 36. Methods: The anti-tumor effect of curcumol was quantified via an MTT assay, colony formation and cycle arrest, respectively. The expressions of ER alpha 36, NCL and the proteins involved in PI3K/AKT signaling were evaluated by western blotting. The interaction between two proteins was detected using co-immunoprecipitation (Co-IP) and an immunofluorescence assay. A mouse xenograft model was established to verify the role of ER alpha 36 in breast cancer cells and curcumol's effect on ER alpha 36 positive cancer cells. Results: Curcumol inhibited the cell growth, caused cell cycle arrest, decreased cell cycle related proteins and inactivated the PI3K/AKT pathway in ER alpha 36 positive breast cancer cells. There is a positive correlation between NCL and ER alpha 36 in breast cancer cells. In addition, ER alpha 36 bound to NCL; the two proteins were distributed in the nucleus, cytoplasm and plasma membrane, where their expression was obviously decreased by curcumol. Moreover, NCL silenced by NCL siRNA blocked the cell cycle progress and inhibited the activation of PI3K/AKT in MDA-MB-231 cells, while overexpressed ER alpha 36 increased the expression of NCL, promoted the cell cycle progress and enhanced the activity of PI3K/AKT in MCF-7 cells. NCL knockdown or ER alpha 36 overexpression attenuated the effect of curcumol on breast cancer cells. Conclusion: Curcumol reduced the proliferation of breast cancer cells by targeting NCL/ER alpha 36 and inactivating the PI3K/AKT pathway.

Automated summary

This study aimed to investigate the effect and mechanism of curcumol on ER alpha 36 positive breast cancer cells, and the relationship between curcumol's target protein NCL and ER alpha 36. The results showed that curcumol reduced the proliferation of breast cancer cells by targeting NCL/ER alpha 36 and inactivating the PI3K/AKT pathway.