Antitumor Effects of Quercetin and Luteolin in MeWo Melanoma Cells: Potential Association with GPER Signaling

Skin cancer takes many forms, but the most dangerous is melanoma, a disease that begins in the pigment-producing cells of the skin. While early-stage melanoma can often be removed with surgery, the disease becomes far more difficult to treat once it spreads to other parts of the body. For decades, scientists have searched for new ways to stop these aggressive cells from growing and moving, looking beyond standard chemotherapy and immunotherapy. One promising avenue involves the body's own hormonal systems. Although melanoma is not typically considered a hormone-driven cancer, researchers have discovered that it possesses receptors—specialized proteins on the cell surface—that can bind to estrogen, a hormone usually associated with reproduction. These receptors, known as G-protein coupled estrogen receptors, act like switches that can trigger rapid changes inside a cell, influencing whether it survives, divides, or dies. The question remains: can natural plant compounds, which mimic the structure of estrogen, flip these switches to stop the cancer?

In a recent study, a team of researchers at the University of Jordan and Al-Zaytoonah University of Jordan set out to test this idea using two common plant compounds found in fruits and vegetables: quercetin and luteolin. These substances belong to a class of chemicals called flavonoids, which are known for their antioxidant properties and potential to fight cancer. The scientists focused their work on MeWo, a specific type of melanoma cell line that is aggressive and capable of spreading, but unlike some other melanoma types, it does not carry a specific genetic mutation often targeted by modern drugs. This made the MeWo cells an important test case for finding treatments that work through different mechanisms. The researchers wanted to see if quercetin and luteolin could slow down the growth of these cells and, if so, whether they did so by interacting with the estrogen receptors on the cell surface.

To find the answer, the team grew the melanoma cells in the laboratory and treated them with varying amounts of the two plant compounds. They watched closely to see how the cells responded over time. The results were clear: both quercetin and luteolin stopped the cancer cells from multiplying. The effect was dose-dependent, meaning that as the amount of the compound increased, the number of living cells decreased. At the highest concentrations tested, the cells were significantly inhibited. The researchers also observed that the cells began to change shape, shrinking and detaching from the surface they were growing on, which are classic signs that a cell is dying. By analyzing the cells under a microscope and using specialized staining techniques, they confirmed that the cells were not just stopping their growth but were actively undergoing a programmed death process known as apoptosis. This is a crucial distinction, as it means the compounds were guiding the cancer cells to destroy themselves rather than just poisoning them indiscriminately.

The study went further to determine exactly how these plant compounds were causing the cells to die. The researchers looked at the internal machinery of the cell, specifically the pathways that control the cell cycle—the series of steps a cell takes to divide. They found that the treatment caused the cells to get stuck at specific checkpoints in this cycle, preventing them from completing the division process. Some cells were halted while copying their genetic material, while others were stopped just before they split into two. This arrest in the cell cycle effectively froze the tumor's ability to expand. Furthermore, the team investigated the signaling pathways that tell the cell whether to live or die. They discovered that the treatment reduced the activity of a survival signal known as the Akt pathway, which often helps cancer cells resist death. At the same time, it increased the activity of another pathway, the ERK pathway, which in this context appeared to be pushing the cells toward apoptosis.

A central part of the investigation was to prove that these effects were indeed linked to the estrogen receptors. To do this, the researchers used a specific blocker, a molecule designed to shut down the estrogen receptors so they could not function. When they added this blocker to the cells before treating them with quercetin or luteolin, the anti-cancer effects were significantly weakened. The cells were much more likely to survive and continue growing compared to when they were treated with the plant compounds alone. This experiment provided strong evidence that the plant compounds were working by interacting with the estrogen receptors on the cell surface. The researchers also found that the compounds increased the number of these receptors on the cell surface, suggesting that the treatment might make the cells even more sensitive to these signals.

The study also examined the ability of the cancer cells to move, a critical factor in how melanoma spreads to other organs. Using a test that measured how many cells could crawl through a tiny barrier, the researchers found that both quercetin and luteolin dramatically reduced the cells' mobility. The treated cells were far less likely to migrate than the untreated ones. This reduction in movement was also dependent on the estrogen receptors, as blocking the receptors restored some of the cells' ability to move. The findings suggest that these plant compounds do not just stop the cancer from growing but also hinder its ability to spread, addressing two of the most dangerous aspects of the disease.

While the study was conducted in a laboratory setting using cells grown in a dish, the results offer a compelling glimpse into how natural compounds might be used to target melanoma. The researchers demonstrated that quercetin and luteolin can effectively slow down the growth of aggressive melanoma cells, force them to die, and stop them from moving, all through a mechanism involving the body's estrogen receptors. The work suggests that these common dietary compounds could potentially be developed into adjuvant therapies, used alongside existing treatments to improve outcomes for patients. However, the authors are careful to note that these findings are specific to the cells in the lab, and further research is needed to understand how these compounds would behave in the complex environment of the human body. The study confirms that the estrogen receptor pathway is a viable target for fighting melanoma and that natural plant compounds hold promise for activating this pathway to stop the disease.