Anticancer compound Oplopantriol A kills cancer cells through inducing ER stress and BH3 proteins Bim and Noxa

Abstract

Oplopantriol-A (OPT) is a natural polyyne from Oplopanax horridus. We show here that OPT preferentially kills cancer cells and inhibits tumor growth. We demonstrate that OPT-induced cancer cell death is mediated by excessive endoplasmic reticulum (ER) stress. Decreasing the level of ER stress either by inactivating components of the unfolded protein response (UPR) pathway or by expression of ER chaperone protein glucose-regulated protein 78 (GRP78) decreases OPT-induced cell death. We show that OPT induces the accumulation of ubiquitinated proteins and the stabilization of unstable proteins, suggesting that OPT functions, at least in part, through interfering with the ubiquitin/proteasome pathway. In support of this, inhibition of protein synthesis significantly decreased the accumulation of ubiquitinated proteins, which is correlated with significantly decreased OPT-induced ER stress and cell death. Finally, we show that OPT treatment significantly induced the expression of BH3-only proteins, Noxa and Bim. Knockdown of both Noxa and Bim significantly blocked OPT-induced cell death. Taken together, our results suggest that OPT is a potential new anticancer agent that induces cancer cell death through inducing ER stress and BH3 proteins Noxa and Bim.

Endoplasmic reticulum stress-induced apoptosis accompanies enhanced expression of multiple inositol polyphosphate phosphatase 1 (Minpp1): a possible role for Minpp1 in cellular stress response

“…The stress response by Minpp1 was directly proportional to the severity of the stress. Collectively, our data imply a physiological role for Minpp1 during cellular stress response (Holczer et al 2015;Jin et al 2014;Puthalakath et al 2007;Stentz et al 2014;Szegezdi et al 2006).…”

“…ER stress-related studies in cancer cells have uncovered Bunfolded protein response^(UPR), autophagy-apoptosis crosstalk, and other shared cell signaling pathways between mitochondria and ER (Naon and Scorrano 2014). It is now being widely accepted that ER as an alternative site of convergence for Bcl-2 family of proteins in the regulation of stress-induced apoptosis (Jin et al 2014). Other studies have identified InsP 3 receptors (InsP 3 R) and activation of pro-apoptotic protein BH3-only proteins including Bim and Puma during ER stress as critical factors (Boehning et al 2004;Greenberg et al 2014;Ivanova et al 2014).…”

Ginseng metabolite protopanaxadiol interferes with lipid metabolism and induces endoplasmic reticulum stress and p53 activation to promote cancer cell death

“…To characterize additional mechanisms that contribute to PPD‐induced cell death, we determined whether PPD can induce ER stress and autophagy, because our previous studies showed that ER stress can induce cell death in part through upregulating Noxa (Jin et al, ; Jin et al, ). XBP1 splicing was rapidly induced by PPD (Figure b).…”

“…The BH3‐only subfamily proteins are antagonized by the Bcl‐2 family of proteins, including Bcl‐2, Bcl‐XL, and MCl‐1, which promote survival (Cory & Adams, ; Thomenius & Distelhorst, ). The expression of BH3‐only proteins are induced by different stress signals, including p53, endoplasmic reticulum (ER) stress, and reactive oxygen species, to induce cell death (Jin et al, ; Nakano & Vousden, ; Oda et al, ; Puthalakath et al, ; Zhang et al, ).…”

“…The expression of BH3-only proteins are induced by different stress signals, including p53, endoplasmic reticulum (ER) stress, and reactive oxygen species, to induce cell death (Jin et al, 2014;Nakano & Vousden, 2001;Oda et al, 2000;Puthalakath et al, 2007;Zhang et al, 2011).…”