Oleuropein-Induced Apoptosis Is Mediated by Mitochondrial Glyoxalase 2 in NSCLC A549 Cells: A Mechanistic Inside and a Possible Novel Nonenzymatic Role for an Ancient Enzyme

Abstract

Oleuropein (OP) is a bioactive compound derived from plants of the genus Oleaceae exhibiting antitumor properties in several human cancers, including non-small-cell lung cancer (NSCLC). Recent evidence suggests that OP has proapoptotic effects on NSCLC cells via the mitochondrial apoptotic pathway. However, the exact molecular mechanisms behind the apoptogenic action of OP in NSCLC are still largely unknown. Glyoxalase 2 (Glo2) is an ancient enzyme belonging to the glyoxalase system involved in the detoxification of glycolysis-derived methylglyoxal. However, emerging evidence suggests that Glo2 may have also nonenzymatic roles in some malignant cells. In the present study, we evaluated whether and how Glo2 participated in the proapoptotic effects of OP in NSCLC A549 cells. Our results indicate that OP is able to induce apoptosis in A549 cells through the upregulation of mitochondrial Glo2 (mGlo2), mediated by the superoxide anion and Akt signaling pathway. Moreover, our data shows that the proapoptotic role of mGlo2, observed following OP exposure, occurs via the interaction of mGlo2 with the proapoptotic Bax protein. Conversely, OP does not alter the behavior of nonmalignant human BEAS-2B cells or mGlo2 expression, thus suggesting a specific anticancer role for this bioactive compound in NSCLC. Our data identify a novel pathway through which OP exerts a proapoptotic effect in NSCLC and suggest, for the first time, a novel, nonenzymatic antiapoptotic role for this ancient enzyme in NSCLC.

The Olive Leaves Extract Has Anti-Tumor Effects against Neuroblastoma through Inhibition of Cell Proliferation and Induction of Apoptosis

“…Moreover, oleuropein induced apoptosis and inhibited the cell proliferation of HepG2 human hepatoma cell line [ 32 ]. More recently, the pro-apoptotic properties of oleuropein were also confirmed by Antognelli et al, who demonstrated that oleuropein induces apoptosis in a non-small cell lung cancer cell line (A549) through the upregulation of mitochondrial glyoxalase 2 [ 33 ]. Anti-tumor effects were also reported for hydroxytyrosol (HT), who reduced the proliferation of human colon adenocarcinoma cells through the inhibition of extracellular signal-regulated kinases (ERK) 1/2 and cyclin D1 [ 34 ].…”

Redox-Sensitive Glyoxalase 1 Up-Regulation Is Crucial for Protecting Human Lung Cells from Gold Nanoparticles Toxicity

“…Human bronchial (BEAS-2B) and alveolar (A549) epithelial cells were obtained from Merck Spa (Milan, Italy). Cells were cultured at the appropriate number in RPMI-1640 (Thermo Fisher Scientific, Monza, Italy), supplemented with 10% heat-inactivated fetal bovine serum (FBS, Thermo Fisher Scientific, Monza, Italy) and 1% antibiotics (penicillin-streptomycin) (Thermo Fisher Scientific, Monza, Italy), at 37 °C in a humidified incubator with 5% CO 2 [ 29 ]. The confluent cells were treated with AuNPs at the final concentrations of 0.8 and 1.6 µg/cm 2 for 3, 24, and 48 h. These concentrations at the indicated time-points were non-toxic or sub-toxic in preliminary experiments (dose-response curves).…”

The Glyoxalase System—New Insights into an Ancient Metabolism

“…Antognelli et al suggested a pro-apoptotic role of Glo2 in non-small-cell lung cancers, and this effect is mediated by a bioactive plant compound called Oleuropein. Another study from the same group revealed that Glo2 can be viewed as a driving force of prostate tumorigenesis and therefore, may represent a novel marker of progression in prostate cancer diagnosis [ 12 , 13 ]. It is a nice illustration, showing that Glo2 may have been overlooked in the context of malignancies and that there is still a lot of space for further studies.…”