Like all cancers, bladder cancer develops when abnormal cells begin to multiply uncontrollably. But what if we could stop its growth?
Previous studies have shown that a protein called PIN1 helps cancers start and progress, but its exact role in tumor development is unclear. Now, cancer biologists at the Salk Institute have discovered that PIN1 is an important driver of bladder cancer and have revealed that it works by triggering the synthesis of cholesterol, a membrane lipid essential for the growth of cancer cells.
After mapping the molecular pathway between PIN1 and cholesterol, the researchers developed an effective treatment regimen that largely stopped tumor growth in their mouse model of cancer. The therapy consists of two drugs: a PIN1 inhibitor called sulfopine, an experimental drug not yet tested in humans, and simvastatin, a statin already used in humans to lower cholesterol levels and reduce the risk of cardiovascular disease.
The findings were published in discovery of cancer, a journal of the American Association for Cancer Research, January 14, 2025.
“We are excited to be the first to identify the role of PIN1 in bladder cancer and describe the mechanism it uses to drive tumor growth,” says senior author Tony Hunter, a professor at the American Cancer Society and holder of the Renato Dulbecco Chair at Salk. “Given the high costs, morbidity and mortality of bladder cancer, we are especially excited to find that targeting the cholesterol pathway with this therapeutic combination was so effective in suppressing bladder tumor growth in mice, and we look forward to seeing this approach explored. in a future clinical trial, once a PIN1 inhibitor is approved for clinical use.”
Bladder cancer is one of the most diagnosed cancers worldwide and the fourth most common cancer among men. It represents a serious threat to public health, as most cases result in costly, lifelong treatment or rapid progression and mortality.
Hunter’s lab originally discovered PIN1 in 1996 as part of their work on phosphorylation., a process in which phosphate molecules attach to proteins to change their structure and function. The lab showed that PIN1 is an enzyme that can recognize a protein when a phosphate is added to the amino acid serine while it is next to the amino acid proline. PIN1 then changes the shape of that protein.
Protein phosphorylation on serine residues next to prolines is known to be an important signaling mechanism that controls cell proliferation and malignant transformation, and its deregulation causes human cancers. PIN1 can target these phosphorylated areas and instigate structural and functional changes in the protein. Still, it’s unclear exactly how this PIN1 activity contributes to tumor formation or what proteins PIN1 might be interacting with in bladder cancer cells.
In search of answers, the team compared normal human bladder cells with bladder cancer cells, in culture dishes and implanted in mice.
First, they showed that PIN1 expression was higher in bladder cancer cells, specifically in the layer of specialized tissue that lines the inside of the urinary tract, called the urothelium. Next, they used genetic scissors to remove the PIN1 gene in the cancer cells. Without PIN1, they observed that fewer cancer cells developed and those that did migrate less aggressively into and beyond the urothelium.
These findings indicated that PIN1 was contributing to the development of bladder cancer, but how?
The researchers returned to the cells lacking PIN1 and looked to see if any other biological processes had been altered. Surprisingly, they found that one of the most affected pathways was the cholesterol synthesis pathway, mediated by a protein called SREBP2. Without PIN1, the bladder cells contained much lower cholesterol levels.
“Cancer cells need a lot of cholesterol to achieve their characteristic excessive growth,” says first author Xue Wang, a postdoctoral researcher in Hunter’s lab. “Our findings show that PIN1 plays an important role in cholesterol production and its deletion leads to reduced cholesterol and therefore less uncontrolled tumor growth.”
Through a series of experiments, the researchers confirmed that PIN1 worked with the SREBP2 protein to stimulate cholesterol production. Deleting PIN1 effectively ended the cancer’s fuel supply, but restoring PIN1 reversed those anticancer effects. Without intervention, the high level of PIN1 in bladder cancer helps tumor growth and metastasis.
How can we stop PIN1? An obvious answer is to inhibit the protein itself, but it is also possible to inhibit an enzyme in the cholesterol pathway that stimulates PIN1. One class of medications, called statins, is already widely used to control cholesterol levels. Statins work by blocking a protein in the cholesterol biosynthesis pathway called HMGCR. The idea was to attack the cholesterol pathway from two angles by combining simvastatin, a widely prescribed statin, to block HMGCR, and sulfopine to deactivate PIN1 and prevent its activation of SREBP2, thus dramatically reducing the ability of bladder cancer cells to produce cholesterol.
When researchers treated mice with bladder cancer tumors with the PIN1 inhibitor sulfopine and the HMGCR inhibitor simvastatin, they found that the combination suppressed cancer cell proliferation and tumor growth; More importantly, the two worked better together than as individual treatments.
“This is likely just one of the many roles that PIN1 plays in cancers,” says Hunter. “However, what is exciting about this discovery is that statins are already used in humans to prevent cardiovascular disease, and our work suggests an opportunity to use statins in combination with other drugs for bladder cancer therapy. And beyond this “We will continue to study whether PIN1 plays a similar role in other cancers, so we hope our findings can improve lives regardless of cancer type.”
The team not only confirmed the role of PIN1 in bladder cancer progression, but also linked PIN1 to cholesterol biosynthesis and created viable treatment solutions to improve treatment outcomes.
Other authors include Yuan Sui and Jill Meisenhelder of Salk, Derrick Lee of UC San Diego, and Haibo Xu of Shenzhen University in China.
The work was supported by the National Institutes of Health (CCSG P30CA023100, CCSG CA014159, 5 R35 CA242443) and a Pioneer Fund Postdoctoral Scholar Award.