Ormeloxifene-induced unfolded protein response contributes to autophagy-associated apoptosis via disruption of Akt/mTOR and activation of JNK

Abstract

Autophagy, a regulated nutrient recycling program can affect both cell survival and cell death. Here, we show that Ormeloxifene (ORM), a selective estrogen receptor modulator approved for oral contraceptive use induces autophagic flux in ovarian cancer cells, which is activated by an ER stress response upstream of autophagy. The ER stress response is characterized by activation of IRE1α, PERK and ATF6 and is under regulation of JNK. Pharmacological inhibition of either autophagy or ER stress increased cell survival, as did silencing of autophagy proteins LC3 and Beclin 1, implying that ORM-induced autophagy is pro-death in nature. Ultrastructural observations of treated cells confirmed stages of autophagic maturation. Caspase-dependent apoptosis succeeded these events and was characterized by generation of reactive oxygen species and disruption of mitochondrial membrane potential. A concomitant inhibition of the Akt/mTOR axis was also observed with possible regulation of Akt by ORM. ORM inhibited tumor growth in ovarian xenograft model and displayed autophagic activity. In summary, in vitro and in vivo results reveal that ORM induces autophagy-associated cell death to attenuate proliferation of ovarian cancer cells. Our results demonstrate that using ORM in combination with ER stress and autophagy modulators could offer better therapeutic outcome in ovarian cancer.

Autophagy induction and antiproliferative effect of a novel curcumin derivative MOMI‐1 on the human lung cancer cells A549

“…Currently, staining cells with acid‐labeled MDC is another rapid method for assessing autophagic activity . We herein continued to use the MDC dye to capture the fluorescent signals of MOMI‐1‐treated A549 cells.…”

Baicalin, a Chinese Herbal Medicine, Inhibits the Proliferation and Migration of Human Non-Small Cell Lung Carcinoma (NSCLC) Cells, A549 and H1299, by Activating the SIRT1/AMPK Signaling Pathway

“…The serine/threonine kinase mechanistic target of rapamycin (mTOR) functions as a mediator of cell survival, which is believed to be oncogenic [ 23 ]. The activation of AMPK might have a negative regulatory effect on mTOR expression, which is known to be resistant to apoptosis by regulating the activation of the caspase cascade and autophagy [ 24 , 25 ]. The results of this study showed that baicalin activated the SIRT1 / AMPK signaling, which further inhibited the phosphorylation of mTOR, resulting in an increase in apoptosis of human NSCLC cells in vitro.…”

The Jun N-terminal kinases signaling pathway plays a “seesaw” role in ovarian carcinoma: a molecular aspect

“…Autophagy is formed by double membrane vesicles and lysosomes, namely the autophagy body, which swallows cell damaged or harmful protein, organelles and complexes and the damaged organelles and protein is degraded by autophagy body. Although autophagy protects both normal and cancer cells from apoptosis, especially in the environment of cytotoxicity, malnutrition and other stimuli, when exceeding a certain limit, autophagy can cause apoptosis of normal and cancer cells [40–42]. Autophagy can generally be divided into at least three major categories: macrophage, micro-autophagy and chaperone-mediated autophagy [43].…”