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.

Matthew J Peirce,Roberta Frosini,Vincenzo N Talesa,Maria F Santolla,Cinzia Antognelli

doi:10.1155/2019/8576961

Matthew J Peirce, Roberta Frosini + Show 3 more

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https://doi.org/10.1155/2019/8576961

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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.

Highlights

In prostate cancer cells, that Glyoxalase 2 (Glo2) is involved in the control of apoptosis, in a glyoxalase 1 (Glo1)-independent and possibly nonenzymatic manner, through the modulation of intracellular levels of p53 [16]
The proapoptotic effect of OP in non-small-cell lung cancer (NSCLC) A549 cells and the related intrinsic apoptosis mechanism were evaluated by measuring the levels of major proteins typically activated in a mitochondrial apoptotic pathway, namely, the antiapoptotic Bcl-2 or Bcl-XL or the proapoptotic Bax proteins, cytochrome c (Cyt c), Apaf-1, and the final executioner caspase-3 [18] by immunoblotting
In order to investigate whether Glo2 could be involved in OP-induced apoptosis, we studied the protein expression and specific activity of the Glo2 enzyme in the mitochondrial and cytosolic fractions of A549 cells exposed to OP

Summary

Introduction

Oleuropein (OP) is an olive-derived polyphenol with an array of pharmacological properties, including anti-inflammatory and antioxidant effects [1], which have fostered intense interest in cancer research as a putative anticancer agent. Lung Cancer and OP Effect on Non-Small-Cell Lung Cancer (NSCLC). While recent years have seen notable advances in the treatment of many cancers, the prognosis for non-small-cell lung cancer (NSCLC), which accounts for 85% of all lung cancer cases, remains dire. Epidemiologic studies have shown an inverse correlation between olive oil consumption and the risk of lung cancer [5,6,7], and recent findings have shown that OP exerts cytotoxic effects, by inducing mitochondrial apoptosis, in NSCLC cells [8, 9]. The molecular mechanisms driving the apoptogenic action of OP in NSCLC remain unclear

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