Researchers have pinpointed new potential targets for treating bladder cancer and have shown that using a mix of existing drugs, such as statins, can help inhibit tumor growth in mice.
Like other types of cancer, bladder cancer occurs when abnormal cells grow uncontrollably. But what if we could slow this growth down?
Previous studies highlighted the involvement of a protein called PIN1 in cancer development, but its specific role in tumor growth remained unclear. Recently, scientists at the Salk Institute discovered that PIN1 significantly contributes to bladder cancer by triggering the production of cholesterol, which is essential for the growth of cancer cells.
By clarifying the molecular link between PIN1 and cholesterol, the researchers developed a treatment strategy that greatly slowed tumor growth in their mouse model of cancer. This approach combines two drugs: sulfopin, an experimental PIN1 inhibitor that hasn’t yet been tested on humans, and simvastatin, a statin that is commonly prescribed to reduce cholesterol and lower the risk of heart disease.
The study was published in Cancer Discovery, a journal from the American Association for Cancer Research, on January 14, 2025.
“We are excited to be the first to reveal the role of PIN1 in bladder cancer and to clarify how it promotes tumor growth,” said senior author Tony Hunter, a professor at the American Cancer Society and the Renato Dulbecco Chair at Salk. “Given the significant financial impact, suffering, and high mortality rates associated with bladder cancer, we are particularly pleased to find that targeting the cholesterol pathway with our treatment strategy effectively reduced tumor growth in mice. We look forward to this approach being tested in upcoming clinical trials once a PIN1 inhibitor is approved for human use.”
Bladder cancer is one of the most commonly diagnosed malignancies worldwide and is the fourth most common cancer among men. It poses a major public health issue, as most cases require expensive, long-term treatment or can lead to swift disease progression and death.
Hunter’s lab first identified PIN1 in 1996 while studying phosphorylation, a mechanism that adds phosphate groups to proteins, altering their structure and functions. The research demonstrated that PIN1 can recognize a protein when a phosphate attaches to the serine amino acid adjacent to proline and subsequently change that protein’s shape.
Phosphorylation of proteins at serine sites near prolines is a critical signaling mechanism for regulating cell growth and malignant changes, and improper regulation can result in human cancers. PIN1 interacts with these phosphorylated regions, causing structural and functional changes to the protein. However, the specific way this function of PIN1 contributes to tumor growth or which proteins it interacts with in bladder cancer cells has remained unclear.
To gain more insight, the research team compared normal human bladder cells to cancerous cells, both in laboratory dishes and when implanted in mice.
Initially, they verified that levels of PIN1 were higher in bladder cancer cells, especially in the urothelium, the tissue lining the urinary tract. They then utilized genetic editing tools to remove the PIN1 gene from the cancer cells. The absence of PIN1 resulted in reduced development of cancerous cells, and those that did emerge were less aggressive in their ability to migrate both within and outside the urothelium.
This confirmed that PIN1 plays a role in the onset of bladder cancer, but the exact mechanism remained to be determined.
The researchers examined the PIN1-deficient cells for any other biological processes that may have changed. They remarkably found that the cholesterol synthesis pathway, controlled by a protein called SREBP2, was significantly influenced. Without PIN1, the bladder cells showed much lower cholesterol levels.
“Cancer cells need a lot of cholesterol to sustain their unchecked growth,” noted first author Xue Wang, a postdoctoral researcher in Hunter’s lab. “Our study shows that PIN1 is crucial for cholesterol production, and removing it leads to reduced cholesterol levels, which hinders tumor growth.”
The researchers ran several tests and demonstrated that PIN1 works together with the SREBP2 protein to promote cholesterol production. By eliminating PIN1, they effectively cut off the cancer’s energy supply. However, reintroducing PIN1 restored the cancer-promoting effects. High PIN1 levels in bladder cancer accelerate tumor growth and spread if uncontrolled.
So, how can we inhibit PIN1? One straightforward approach would be to block the protein itself, but we could also target an enzyme in the cholesterol pathway that PIN1 stimulates. Statins are one class of drugs already widely used to manage cholesterol. They work by inhibiting a cholesterol biosynthesis protein called HMGCR. The strategy was to tackle the cholesterol pathway from two sides by combining simvastatin, a commonly prescribed statin that blocks HMGCR, with sulfopin, which shuts down PIN1 and curtails its stimulation of SREBP2, thereby significantly reducing cholesterol production in bladder cancer cells.
After treating the mice with bladder cancer tumors using both the PIN1 inhibitor sulfopin and the HMGCR inhibitor simvastatin, the researchers found that the combination significantly reduced cancer cell growth and tumor spread, demonstrating a synergistic effect when the two drugs were used together rather than alone.
“This is likely just one of the many roles that PIN1 plays in various cancers,” stated Hunter. “What makes this discovery particularly exciting is that statins are already prescribed to prevent cardiovascular disease in humans, and our results suggest the potential to combine statins with other treatments for bladder cancer. We will also investigate whether PIN1 has a similar function in other cancers, enabling our research to potentially benefit a range of cancer types.”
The research team not only confirmed the involvement of PIN1 in the progression of bladder cancer but also connected it to cholesterol production and developed promising treatment strategies to enhance patient outcomes.
Other contributors to this study include Yuan Sui and Jill Meisenhelder from Salk, Derrick Lee from UC San Diego, and Haibo Xu from Shenzhen University in China.
This research was supported by the National Institutes of Health (CCSG P30CA023100, CCSG CA014159, 5 R35 CA242443) and a Pioneer Fund Postdoctoral Scholar Award.
