Plumbagin sensitizes breast cancer cells to tamoxifen-induced cell death through GRP78 inhibition and Bik upregulation

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.

The Effect of Afatinib Treatment in Non-small Cell Lung Cancer Cells

“…Our data seems to be consistent with research conducted in breast cancer. The researchers proposed that plumbagin (anticancer drug) induces apoptosis in estrogenpositive breast cancer cells through HSPA5 (GRP78) inhibition (18). Nevertheless, in accordance to our studies afatinib by itself induces apoptosis and mRNA level of HSPA5 decreases.…”

“…In our results, it seems that apoptosis is caused by afatinib treatment and HSPA5 mRNA level reduction depends on morphological changes. However, our interpretations require further experiments, although it appears there is some connection between anticancer drugs apoptotic effect and HSPA5 in cancer cells (18).…”

Targeting protein quality control pathways in breast cancer

“…For this reason, the development of specific BiP inhibitors represents an important goal. In fact, a natural product of the naphthoquinone family, plumbagin, was identified that initiates cell death in ER-positive breast cancer cells by upregulating BIK levels [ 219 , 220 ]. Plumbagin-mediated BiP inhibition also sensitized breast cancer cells to tamoxifen-mediated cell death.…”

“…Plumbagin-mediated BiP inhibition also sensitized breast cancer cells to tamoxifen-mediated cell death. In addition, BiP knock down impaired the plumbagin-mediated increase in Bik, suggesting an inhibitory role of this compound on BiP-mediated downregulation of BIK in breast cancers [ 220 ]. Overall, BiP is emerging as a novel target to predict cancer outcomes and therapeutic options [ 209 , 221 – 223 ].…”

Compensatory increases of select proteostasis networks after Hsp70 inhibition in cancer cells

“…Another emerging target is the cytosolic Hsp70 molecular chaperone, which is upregulated in many cancers and inhibits multiple steps in the apoptotic pathway (Garrido et al, 2006;Santarosa et al, 1997;Uozaki et al, 2000). Inhibition of Hsp70 or the ER luminal homolog, BiP (also known as GRP78 and HSPA5), kills colorectal carcinomas, breast cancers, leukemia cells, glioblastomas and ovarian cancer cells (Cerezo et al, 2016;Guo et al, 2005;Kawiak et al, 2017;Lee, 2001Lee, , 2007Ni et al, 2009;Powers et al, 2008Powers et al, , 2009Sabnis et al, 2016). Furthermore, Hsp70 promotes chemotherapeutic resistance, and Hsp70 induction predicts metastasis in several cancers (Brodsky and Chiosis, 2006;Calderwood and Gong, 2016;Nanbu et al, 1998;Patury et al, 2009;Powers et al, 2009).…”