Putting a lid on excess cholesterol to halt bladder cancer cell growth

(Press-News.org) LA JOLLA (January 14, 2025)—Like all cancers, bladder cancer develops when abnormal cells start to multiply out of control. But what if we could put a lid on their growth?

Previous studies showed that a protein called PIN1 helps cancers initiate and progress, but its exact role in tumor development has remained unclear. Now, cancer biologists at the Salk Institute have discovered that PIN1 is a significant driver of bladder cancer and revealed that it works by triggering the synthesis of cholesterol—a membrane lipid essential for cancer cells to grow.

After mapping out the molecular pathway between PIN1 and cholesterol, the researchers developed an effective treatment regimen that largely halted tumor growth in their mouse model of cancer. The therapy consists of two drugs: a PIN1 inhibitor called sulfopin, an experimental drug not yet tested in humans, and simvastatin, a statin that is already used in humans for lowering cholesterol levels to reduce the risk of cardiovascular disease.

The findings were published in Cancer Discovery, a journal of the American Association for Cancer Research, on January 14, 2025.

“We’re excited to be the first to identify PIN1’s role in bladder cancer and to describe the mechanism it uses to drive tumor growth,” says senior author Tony Hunter, American Cancer Society professor and holder of the Renato Dulbecco Chair at Salk. “Given the high costs, morbidity, and mortality rates for bladder cancer, we’re especially thrilled to discover that targeting the cholesterol pathway with this therapeutic combination was so effective in suppressing bladder tumor growth in mice, and we hope to see 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 poses a serious threat to public health, as most cases result in either expensive, lifelong treatment, or rapid progression and mortality.

Hunter’s lab had originally discovered PIN1 in 1996 as a part of its work on phosphorylation, a process in which phosphate molecules are tacked onto 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’s next to the amino acid proline. PIN1 then changes that protein’s shape.

Phosphorylation of proteins at serine residues next to prolines is known to be a major signaling mechanism controlling cell proliferation and malignant transformation, and its dysregulation causes human cancers. PIN1 can target these phosphorylated areas and instigate structural and functional changes to the protein. Still, it’s been unclear exactly how this PIN1 activity contributes to tumor formation or which 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 demonstrated that PIN1 expression was higher in bladder cancer cells—specifically in the specialized tissue layer that lines the inside of the urinary tract, called the urothelium. Then, they used genetic scissors to eliminate the PIN1 gene in the cancer cells. Without PIN1, they saw fewer cancerous cells develop, and those that did develop migrated less aggressively within 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 that were missing 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 levels of cholesterol.

“Cancer cells need a lot of cholesterol to accomplish their trademark excess 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 removing it leads to lower cholesterol and therefore less out-of-control tumor growth.”

Through a series of experiments, the researchers confirmed that PIN1 was working with the SREBP2 protein to stimulate cholesterol production. Removing PIN1 effectively put a lid on the cancer’s fuel supply, but reinstating PIN1 reversed those anti-cancer effects. Without intervention, the high level of PIN1 in bladder cancer assists in tumor growth and metastasis.

How can we stop PIN1? One obvious answer is to inhibit the protein itself, but it’s also possible to inhibit an enzyme in the cholesterol pathway that PIN1 stimulates. One class of drugs, called statins, is already very 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 sulfopin to disable PIN1 and prevent its activation of SREBP2, thus drastically reducing the ability of the bladder cancer cells to make cholesterol.

When the researchers treated the mice with bladder cancer tumors with the PIN1 inhibitor sulfopin and the HMGCR inhibitor simvastatin, they found the combination suppressed cancer cell proliferation and tumor growth—importantly, the two worked better in tandem than as individual treatments.

“This is likely just one of many roles that PIN1 plays in cancers,” says Hunter. “What’s exciting about this discovery, though, is that statins are already in human use 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’ll continue to study whether PIN1 plays a similar role in other cancers, so our findings can hopefully improve lives regardless of cancer type.”

Not only did the team confirm PIN1’s role in bladder cancer progression, they also connected 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.

About the Salk Institute for Biological Studies:

Unlocking the secrets of life itself is the driving force behind the Salk Institute. Our team of world-class, award-winning scientists pushes the boundaries of knowledge in areas such as neuroscience, cancer research, aging, immunobiology, plant biology, computational biology, and more. Founded by Jonas Salk, developer of the first safe and effective polio vaccine, the Institute is an independent, nonprofit research organization and architectural landmark: small by choice, intimate by nature, and fearless in the face of any challenge. Learn more at www.salk.edu.

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