Abstract
The glucose regulated protein 78 (GRP78) is a major chaperone of the endoplasmic reticulum, and a prosurvival component of the unfolded protein response. GRP78 is upregulated in many types of cancers, including breast cancer. Research has suggested that GRP78 overexpression confers chemoresistance to anti-estrogen agents through a mechanism involving the inhibition of a pro-apoptotic BH3-only protein, Bik. In the present research the role of plumbagin, a naturally occurring naphthoquinone, in GRP78-associated cell death inhibition was examined. The results demonstrated that plumbagin inhibits GRP78 activity and GRP78 inhibition contributes to plumbagin-mediated cell death induction. Furthermore, Bik upregulation was associated with plumbagin-induced cell death and an increase in plumbagin-mediated Bik induction was observed upon GRP78 downregulation. Plumbagin sensitized estrogen-positive breast cancer cells to tamoxifen and the association of GRP78 inhibition and Bik upregulation in plumbagin-mediated cell sensitization was shown. Collectively, the results of this research suggest that plumbagin inhibits the antiapoptotic activity of GRP78 leading to Bik upregulation and apoptosis induction, which contributes to the sensitization of breast cancer cells to tamoxifen.
Highlights
Antiproliferative activity towards various cancer cell lines[20,21,22] and its anti-cancer properties have been shown in studies in vivo[23,24,25]
The results of the MTT assay showed a dose-dependent decrease in cell viability induced by plumbagin, and the obtained IC50 values for MCF-7 and T47D cells were of 3.5 μM and 1.5 μM, respectively (Fig. 1A)
These results suggest the involvement of GRP78 inhibition and Bcl-2-interacting killer (Bik) upregulation by plumbagin in its sensitizing effects to tamoxifen in estrogen-positive breast cancer cells
Summary
Antiproliferative activity towards various cancer cell lines[20,21,22] and its anti-cancer properties have been shown in studies in vivo[23,24,25]. In vivo studies have shown that plumbagin significantly inhibits the growth of breast tumor xenografts in mice without toxic side-effects[24]. Recent studies showed that plumbagin inhibits the growth of endocrine-resistant breast cancer cells and increases the sensitivity of these cells to tamoxifen-induced cell death[36]. These findings prompted us to further determine the mechanism of plumbagin-mediated sensitization of breast cancer cells to tamoxifen. The effects of plumbagin on GRP78 inhibition and its involvement in plumbagin-mediated cell death induction were examined. The association between GRP78 inhibition in plumbagin-mediated sensitization of breast cancer cells to tamoxifen was examined
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