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Oleuropein Induces Cytotoxicity and Peroxiredoxin Over-expression in MCF-7 Human Breast Cancer Cells

KATHERINE JUNKINS, MARGARET RODGERS and SHELLEY A. PHELAN
Anticancer Research October 2023, 43 (10) 4333-4339; DOI: https://doi.org/10.21873/anticanres.16628

Abstract

Background/Aim: As a fundamental staple of the Mediterranean diet, olive oil has long been recognized for its health benefits, including its ability to reduce cardiovascular and neurological disease. Oleuropein is the primary phenolic chemical found in all parts of the olive tree, especially in the leaves and fruit. Oleuropein exhibits anti-inflammatory and antioxidant properties, and has been associated with cancer inhibition in various animal and cell models. We investigated the effects of oleuropein on the MCF-7 human breast cancer cell line, and compared it to the non-cancerous MCF-10A breast epithelial line. Materials and Methods: Both cell lines were treated with two different concentrations of oleuropein for 48 and 72 hours. Cytotoxicity, apoptosis, and peroxiredoxin expression were measured. Results: Forty-eight hours of oleuropein treatment induced cytotoxicity in MCF-7 cells, whereas it had no effect on MCF-10A cells. Furthermore, oleuropein-induced cytotoxicity in MCF-7 cells involved a measurable increase in apoptosis. Oleuropein treatment of MCF-7 cells significantly and dramatically increased expression of all six peroxiredoxin mRNAs (Prdx1-Prdx6), whereas oleuropein treatment of MCF-10A cells resulted in only a small increase in Prdx1 and Prdx6 expression, with no change in the expression of the other peroxiredoxins. Together, these data demonstrate differential susceptibility to oleuropein-induced cell death between the two lines, and differential regulation of peroxiredoxins. Conclusion: Oleuropein-induced over-expression of peroxiredoxins in MCF-7 cells may either facilitate its cancer-specific cytotoxicity or, alternatively, is a consequence of an altered response of cancer cells.

Key Words:

The Mediterranean diet is regularly cited as one of the healthiest diets in the world. One of its hallmark features is the use of olive oil, which has a long history of demonstrated health benefits (1). There is much evidence that olive oil and olive leaf extracts are associated with reduced cardiovascular and neurological disease (1, 2), as well as anticarcinogenic and antioxidant properties (3-6). Many of the beneficial properties of the plant have been attributed to its primary phenolic compound oleuropein, which is predominantly found in the leaves, but also within the fruit and other parts of the plant (7, 8). Oleuropein is a secoiridoid glycoside consisting of hydroxytyrosol, elenolic acid, and a glucose molecule. Oleuropein has been shown to possess antioxidant, antimicrobial and anti-inflammatory properties, and its phenolic structure and ability to reduce reactive oxygen species (ROS) has been associated with many of its health benefits (1, 2, 7). The compound has also been well documented for reducing hypertension, with evidence that it improves mitochondrial function through the Nrf2 signaling pathway, protecting the hypothalamus from oxidative stress in a rat model (9).

Oleuropein also elicits significant anti-cancer effects, including proliferation inhibition and apoptosis induction, in a wide variety of cancer cell types (5-7, 10). Several studies have demonstrated efficacy of oleuropein in inhibiting cell growth and inducing apoptosis in various breast cancer cell lines (11-15). Notably, oleuropein demonstrates specific anticancer action against the HER2 positive human breast cancers, including the MCF-7 cell line, where it was shown to inhibit cell growth, motility, and invasiveness (6). Other evidence has demonstrated a concentration-dependent inhibition of proliferation and induction of apoptosis in MCF-7 cells treated with oleuropein (11). Support for the in vivo treatment potential of oleuropein has also been shown, as an oleuropein-enriched diet prevented tumor growth and metastasis of MCF-7 tumor xenografts in mice (13). Despite the evidence that oleuropein possesses antioxidant function, pro-oxidant activity of oleuropein has been demonstrated in various cell lines including MCF-7 cells (6, 14). This suggests a complex role for oleuropein in cancer cells.

As a way to combat oxidative stress, cells synthesize a variety of antioxidants to counterbalance elevated ROS. Cellular antioxidants help to control ROS levels in order to facilitate normal cell signaling and necessary enzymatic reactions, without causing damage to lipids and proteins. Peroxiredoxins (Prdx) are thiol-specific antioxidant proteins found within all mammalian cells and are responsible for reducing cellular peroxides and preventing or repairing cellular oxidative damage (16). Prdx proteins are also known to possess molecular chaperone activity, and can influence various signal transduction pathways (16). There are six members of the Prdx family, with characteristic cellular locations and tissue distribution. It’s been widely reported that Prdx expression is upregulated in many cancers, with several studies demonstrating elevated Prdx levels in breast cancer (17-19). A previous report from our lab analyzing Prdx protein expression in tumor vs. non-tumor breast tissue from patients showed elevated Prdx expression in breast tumors in most patients (20), and more recently, a significant upregulation of mRNA expression of Prdx1-5 was confirmed in breast cancer tissue compared to healthy tissue (21). Furthermore, our laboratory previously showed elevated levels of Prdx1-5 in MCF-7 cells, compared to the non-cancerous MCF-10A cells, and we demonstrated that lowering Prdx levels in MCF-7 cells using siRNA led to a decrease in cell resistance to the chemotherapy agent doxorubicin (22). With the increased interest in the anti-cancer effects of natural antioxidant compounds, studies have begun to examine the effect of these chemicals on antioxidant protein expression and related signal transduction pathways. While many studies have shown that oleuropein can alter regulation of genes involved in oncogenic and apoptotic pathways, there have been no published reports on the effect of oleuropein on peroxiredoxin expression in MCF-7 cells.

Given the well-documented anticancer effects of oleuropein, and the complex role of peroxiredoxins in cancer cells, it is important to understand if this antioxidant family of genes is regulated by oleuropein. The present study further examined oleuropein’s anticancer activity by comparing its effect on cytotoxicity and peroxiredoxin expression in the MCF-7 breast cancer line and the non-cancerous MCF-10A cell line. We hypothesized that MCF-7 cells would be more susceptible to oleuropein-induced cytotoxicity, and may display altered Prdx expression.

Materials and Methods

Cell lines and treatments. Two cell lines were used for these studies. The human MCF-7 breast cancer cell line and MCF-10A non-cancerous breast epithelial cell line were purchased from ATCC (Manassas, VA, USA). MCF-7 cells were cultured in Eagles Minimal Essential Media (ATCC cat number: 30-2003) containing 5% fetal bovine serum (ATCC cat number: 30-2020) and 50 ng/ml insulin (Sigma Aldrich, St. Louis, MO, USA). MCF-10A cells were cultured in Mammary Epithelial Basal Medium (MEBM) with bullet kit supplements (Lonza, Walkersville, MD, USA). Both lines were grown and maintained at 37°C in a humidified 5% CO2 incubator. Oleuropein was purchased from LK Laboratories, Inc (St. Paul, MN, USA). A 100 mg/ml stock solution was prepared in 70% ethanol and stored at −20°C. For all cell experiments, cells were seeded into 96-well plates and viable cells were quantified using a hemacytometer and a trypan blue exclusion assay and. For each experiment, cells were treated with either 70% ethanol (vehicle control), 50 μg/ml or 200 μg/ml oleuropein and incubated for 48 or 72 h.

Measurement of cytotoxicity. Cells were plated at a density of 1.0×104 cells per well in a 96-well plate in replicates of 8-10. Cells were treated with 50 μg/ml or 200 μg/ml oleuropein (or an equal volume of 70% ethanol as vehicle control). At 48 h post treatment, 40 μl of media was removed and tested for LDH levels using the colorimetric lactate dehydrogenase (LDH) Assay (Promega, Madison, WI, USA). Absorbance was measured at 490 and media-only (no cells) samples were used to obtain the blank-subtracted absorbances.

Measurement of apoptosis & microscopy. Cells were plated at a density of 1.0×104 cells per well in a 96-well plate in replicates of three. Cells were treated with 50 μg/ml or 200 μg/ml oleuropein (or an equal volume of 70% ethanol as vehicle control). At 48 h post treatment, cells were rinsed with 1X PBS and apoptosis was assayed using the Annexin apoptotic assay (ThermoFisher, Waltham, MA, USA), which includes a green fluorescent labeling of membrane Annexin V, and propidium iodide counterstaining of nuclei. Cells were imaged using phase contrast, as well as red/green fluorescence microscopy.

Measurement of peroxiredoxin expression. To measure peroxiredoxin expression, cells were plated at a density of 1×104 cells/well in a 96-well plate in replicates of three. Cells were treated with ethanol or oleuropein for 48 h and subsequently lysed and RNA isolated using the Cells-to-CT (Applied Biosystems, Waltham, MA, USA) reagents. RNA was reverse transcribed with using reverse transcriptase enzyme and buffer (Applied Biosystems) and Taqman Real Time PCR Assays were conducted using Applied Biosystems primer/probes specific to each of the six mammalian peroxiredoxin genes. These included human-specific TaqMan assays for Prdx1 (Hs00602020), Prdx2 (Hs03044902), Prdx3 (Hs00428953), Prdx4 (Hs00197384), Prdx5 (Hs00738905) and Prdx6 (Hs00705355). An 18S rRNA primer/probe (Applied Biosystems cat#4333760F) was used as an endogenous control for all Real Time PCR reactions. Real Time PCR reactions were performed in triplicate for each sample, and Ct (Cycle threshold) values were measured using the Applied Biosystems. The double delta Ct (ΔΔCt) method was then used to calculate relative quantification (RQ) as a measure of relative expression.

Statistical analysis. For each experiment, the means of parameter were statistically compared using a two-tailed student’s t-test, assuming equal variances. p<0.05 was considered statistically significant.

Results

We first examined the cytotoxic effects of oleuropein in the two cell lines. To do this, we treated the cells with oleuropein or ethanol for 48 h and tested media for LDH levels released from dying cells. As shown in Figure 1, 50 μg/ml oleuropein did not induce cytotoxicity at either time point in MCF-7 cells. Similarly, MCF-10A cells were not affected by oleuropein at this concentration. However, treatment with 200 μg/ml oleuropein resulted in a significant increase in released LDH (over 100%) by 48 h. In contrast, MCF-10A cells showed no cytotoxicity by 48 h.

Figure 1.
Figure 1.

The cytotoxic effect of oleuropein on MCF-7 vs. MCF-10A cells. Cells were treated with ethanol, 50 μg/ml oleuropein (Low Ol) or 200 μg/ml oleuropein (High Ol) for 48 h. Media was collected at 48 h and used for an LDH release assay to measure cytotoxicity. Absorbances were measured at 490 nm and blank-corrected. Averages from replicates (n=8-10) are shown, +/− std deviations. *p<0.05.

To further explore the cytotoxic effects on MCF-7 cells, we determined whether cell death involved apoptosis. We treated the cells with ethanol or oleuropein as described above for 48 h and then conducted an apoptosis assay. As shown in Figure 2, we observed a dose-dependent increase in cells positive for propidium iodide and membrane-staining of Annexin V in oleuropein-treated cells. These data strongly suggest apoptotic death in oleuropein-treated MCF-7 cells.

Figure 2.
Figure 2.

Oleuropein-induced apoptosis in MCF-7 cells. Cells were treated with ethanol, 50 μg/ml oleuropein (Low Ol) or 200 μg/ml oleuropein (High Ol) for 48 h. Cells were then assayed for apoptosis using propidium iodide and Annexin V staining. Cells were subsequently imaged with phase contrast microscopy (top) and red/green fluorescence microscopy (bottom). Representative images (100×) are shown for cells treated with ethanol control (left), 50 μg/ml oleuropein (center) or 200 μg/ml oleuropein (right).

To understand if oleuropein differentially affects antioxidant gene expression between the MCF-7 and MCF-10A cell lines, we compared the effect of oleuropein treatment on peroxiredoxin expression in the two lines after 48 h of treatment using real time PCR (Figure 3). At the lower 50 μg/ml concentration of oleuropein, there was virtually no change in expression of any of the peroxiredoxin genes in MCF-7 cells. In contrast, at the highest concentration of 200 μg/ml, oleuropein treatment led to a marked induction in the expression of all six peroxiredoxins in the MCF-7 cell line. The magnitude of this increase was substantial, and ranged from approximately 70% increase for Prdx4 and Prdx5, 100% increase for Prdx2, Prdx3 and Prdx6, and 200% increase for Prdx1. In contrast, MCF-10A cells showed a 50% elevation in Prdx1 expression with both concentrations of oleuropein, yet no induction of Prdx2, Prdx3, Prdx4 and Prdx5 was observed with either concentration. Prdx6 expression was moderately increased with both concentrations, showing a statistically significant effect (approximately 25% increase) at the higher concentration. Together, these data show very different oleuropein-induced peroxiredoxin responses in the two cell lines.

Figure 3.
Figure 3.

Differential regulation of peroxiredoxins by oleuropein in MCF-7 vs. MCF-10A cells. Cells were treated with ethanol, 50 μg/ml oleuropein (Low Ol) or 200 μg/ml oleuropein (High Ol) for 48 h. Real Time PCR was used to measure mRNA expression for Prdx1-Prdx6. Average RQ values for MCF-7 (left) and MCF-10A (right) are shown (n=3), +/− std deviations. *p<0.05.

Discussion

Our results indicated significant differences in the response of MCF-7 and MCF-10A cell lines to oleuropein. We found that a high dose (200 μg/ml) of oleuropein induced death of MCF-7 cells within 48 h, and demonstrated that this process involved apoptosis. In contrast, there was no significant cytotoxicity was observed towards MCF-10A cells at the same dose. Upon examination of peroxiredoxin levels in both lines, we found that 48 h of 200 μg/ml oleuropein treatment caused a marked upregulation of all six peroxiredoxin genes in MCF-7 cells, with the most significant increase in Prdx1. In contrast, oleuropein treatment of MCF-10A cells caused no significant change in the expression of Prdx2, Prdx3, Prdx4 and Prdx5, and resulted in only a modest increase in Prdx1 and Prdx6. Overall, the MCF-7 and MCF-10A cells showed markedly different responses to oleuropein in terms of cytotoxicity and peroxiredoxin expression.

Our cytotoxicity data in MCF-7 cells is consistent with other published studies. Oleuropein has been previously shown to reduce cell proliferation and increase apoptosis in MCF-7 cells (11). This study reported that 200 μg/ml oleuropein significantly reduced viability in these cells (11), which is similar to our results. The higher resistance to oleuropein-induced cytotoxicity that we observed in the MCF-10A cell line is also noteworthy. Although few studies examined the effect of oleuropein on non-cancerous breast cells to date, our results are consistent with a report showing lower oleuropein-induced cytotoxicity in these cells (23), suggesting a different cellular response of healthy cells.

While the precise anti-cancer mechanism of oleuropein in MCF-7 cells is unknown, specific studies have provided some insights. Cell cycle analysis by Han et al. found that oleuropein induced a significant block in the G1 to S phase transition in MCF-7 cells (11). In another study, the antiproliferative effect of oleuropein against MCF-7 cells was reported to involve inhibition of estradiol (E2)-dependent activation of the MAPK protein (ERK1/2) (12). Furthermore, oleuropein treatment of MCF-7 cells has been shown to induce upregulation of pro-apoptotic genes such as p53 and p21, and down-regulation of antiapoptotic genes including Bcl-2 (24). Oleuropein also has also been shown to function through the regulation of the NF-kB cascade in estrogen receptor negative breast cancer cells, including MCF-7s (15). Given that the signal transduction pathways controlling cell growth, proliferation and apoptosis are differentially regulated in MCF-7 cells as compared to normal breast epithelial cells, it is possible that oleuropein-induced regulation of these key oncogenes and tumor suppressors might explain the observed differences between the two lines in our study. While the antioxidant activity of oleuropein has been well documented in healthy tissue, it is also important to note that oleuropein exhibits pro-oxidant behavior in cancer cells, including breast cancer (14). This provides another possible mechanism for the differential cellular responses between the two cell lines used in this study.

Our observation that oleuropein induces a profound upregulation of Prdx gene expression in MCF-7 cells, but not MCF-10A cells, is intriguing. Since overexpression of peroxiredoxins in cancer is hypothesized to be a cellular adaptation to chronically elevated ROS levels found in cancer cells, it is possible that further peroxiredoxin overexpression in response to oleuropein is a cellular response to oleuropein acting as a pro-oxidant in these cells. This notion is supported by the previously demonstrated pro-oxidant activity of oleuropein in cancer cells (14), but not normal cells. Given that oleuropein leads to cytotoxicity in MCF-7 cells, Prdx over-expression may also be the downstream result of aberrant cell signaling in these cells. Regardless of the mechanism for up-regulation, it will be important to understand the role Prdxs in the MCF-7 cell response. Since Prdx proteins can act as both antioxidants and chaperones, elevated levels in MCF-7 cells could result in changes in one or both activities, which could either help to facilitate the cytotoxicity, or may simply represent the cells’ attempt to combat elevated ROS. It is important to note that Prdx1, in particular, has been shown to have a dominant role in protecting MCF-7 cells from pro-oxidant agents, as targeted disruption of Prdx1 using CRISPR specifically inhibited cell proliferation in MCF-7 cells but not normal cells, and sensitized these cancer cells to the effects of pro-oxidants (25). Our demonstration of a particularly large induction of Prdx1 by oleuropein in MCF-7 cells is consistent with a unique role for Prdx1 in the cell’s defense. Further examination of the role of oleuropein-induced peroxiredoxin upregulation in the MCF-7 response will be extremely helpful in understanding its potential as an anticancer agent.

Conclusion

Overall, the MCF-7 and MCF-10A cells showed markedly different responses to oleuropein in terms of cytotoxicity and peroxiredoxin expression. Future studies into the differential regulation of peroxiredoxins by oleuropein in MCF-7 and MCF-10A cells will be extremely useful for understanding the cancer-specific effects of oleuropein. Additionally, identifying the cellular pathways by which oleuropein functions in breast cancer cells, and examining the precise role of peroxiredoxins in this process, will allow us to better assess the therapeutic potential of oleuropein in breast cancer.

Acknowledgements

This work was supported by the Department of Biology and the Science Institute at Fairfield University.

Footnotes

  • Authors’ Contributions

    The first and second author have contributed equally to this work. The third author is the senior author and principal investigator.

  • Funding

    This work was funded by the Department of Biology and the Science Institute at Fairfield University.

  • Conflicts of Interest

    There are no financial or non-financial conflicts of interest to declare in relation to this study.

  • Received July 5, 2023.
  • Revision received July 27, 2023.
  • Accepted July 28, 2023.

This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY-NC-ND) 4.0 international license (https://creativecommons.org/licenses/by-nc-nd/4.0).

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Oleuropein Induces Cytotoxicity and Peroxiredoxin Over-expression in MCF-7 Human Breast Cancer Cells
KATHERINE JUNKINS, MARGARET RODGERS, SHELLEY A. PHELAN
Anticancer Research Oct 2023, 43 (10) 4333-4339; DOI: 10.21873/anticanres.16628
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