Role of ICI-182,780 as a Repurposed Drug to reduce Glioblastoma Stemness sustained by Estrogen signaling: First evidence of GLI-1 as co-activator of ERα

Glioblastoma is the most aggressive and deadly form of primary brain cancer in adults. Even with the best current treatments, which combine surgery, radiation, and chemotherapy, the disease almost always returns, and survival rates remain tragically low. A major reason for this failure lies in a small group of cells within the tumor known as glioblastoma stem cells. These cells act as a resilient reservoir; they can survive standard therapies, regenerate the tumor, and drive the cancer's ability to spread and resist treatment. For years, scientists have searched for the specific molecular switches that keep these dangerous stem cells alive and active, hoping to find a way to turn them off.

Recent research has begun to connect two distinct biological systems that were previously thought to operate separately within the brain. One system involves the renin-angiotensin system, a network of proteins and receptors best known for regulating blood pressure but also found locally in the brain, where it can influence cell growth. The other involves estrogen signaling, the pathway through which the hormone estrogen affects cells. While estrogen is often associated with reproductive health, it also plays a role in how certain brain tumors behave. The question researchers faced was whether these two systems talk to each other to fuel the growth of glioblastoma stem cells, and if so, whether blocking that conversation could offer a new way to treat the disease.

A team of scientists from the University of Calabria and the Magna Graecia University of Catanzaro in Italy set out to investigate this exact connection. They focused on a specific molecule called Angiotensin II, which is part of the blood-pressure system, and asked whether it helps glioblastoma stem cells survive by hijacking estrogen signaling. To test this, they used human glioblastoma cells grown in the laboratory, including specialized clusters of stem cells that mimic the tumor's behavior more closely than standard flat cell cultures. They exposed these cells to Angiotensin II and watched how the cells responded, while also testing whether a drug designed to destroy estrogen receptors could stop the process.

The researchers discovered that Angiotensin II does indeed trigger a chain reaction that leads to the activation of estrogen receptors on the surface of the cancer cells. This activation sets off a rapid signaling cascade inside the cell, involving a pathway known as PI3K/AKT, which is a common route cells use to grow and survive. Crucially, the team found that this estrogen-driven signal leads to the activation of a protein called GLI-1. GLI-1 is a master regulator that controls genes responsible for stemness—the ability of a cell to remain undifferentiated and self-renewing. What made this discovery particularly significant was how GLI-1 was turned on. The researchers showed that it happened without the usual trigger from the classic Hedgehog signaling pathway, which is the standard way GLI-1 is activated in many cancers. Instead, the estrogen signal bypassed the normal route, directly boosting GLI-1 levels through the PI3K/AKT pathway.

To understand the full impact of this connection, the scientists looked at how the cells behaved. When they treated the cells with Angiotensin II, the stem cells formed more clusters, grew larger, and became more invasive, spreading out aggressively in their three-dimensional culture models. They also produced higher levels of markers that identify stem cells, such as CD133, and increased the expression of genes that maintain their stem-like state. However, when the researchers added a drug called ICI-182,780, which completely removes estrogen receptors from the cells, these aggressive behaviors stopped. The stem cells stopped forming new clusters, their invasive growth slowed, and the levels of stemness markers dropped significantly. This demonstrated that the entire process depended on the presence of functional estrogen receptors.

The study went a step further to reveal a surprising partnership between the proteins involved. The researchers found that GLI-1 does not just act as a passive result of the signaling chain; it physically binds to the estrogen receptor itself. Once attached, the two proteins work together to turn on specific genes that drive tumor growth, such as the gene for Cyclin D1, which helps cells divide. This means that GLI-1 acts as a co-activator, essentially helping the estrogen receptor work even harder. The team confirmed this physical interaction using specialized microscopy and genetic tests, showing that when the estrogen receptor is removed, GLI-1 can no longer bind to the DNA to promote growth.

To ensure these findings were not just a laboratory curiosity, the researchers examined data from thousands of patients with glioblastoma stored in public medical databases. They found that patients whose tumors had high levels of both GLI-1 and the estrogen receptor tended to have a much shorter survival time compared to those with lower levels of these proteins. This correlation suggested that the mechanism they observed in the lab is indeed active in human patients and is linked to the most aggressive forms of the disease. Furthermore, they noted that while blocking the Angiotensin II receptor with a common blood pressure medication called Losartan had some effect, it was not as powerful as removing the estrogen receptor. This indicated that while Angiotensin II starts the process, the estrogen signaling pathway is the essential engine driving the stem cells.

The implications of this work point toward a potential new strategy for treatment. Since the drug ICI-182,780, which is already known for its ability to degrade estrogen receptors, was able to effectively dismantle the stemness and invasiveness of the tumor cells in the lab, the researchers propose that repurposing this drug could be a viable approach for glioblastoma. By targeting the estrogen signaling that sustains the stem cells, it may be possible to break the cycle of recurrence and resistance that currently makes glioblastoma so difficult to cure. The study highlights that the cancer stem cells rely on a specific, non-canonical pathway where estrogen and the GLI-1 protein team up, offering a clear target for future therapies that could complement existing treatments.