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New Discovery Unveils Potential Bladder Cancer Treatment Targeting Cholesterol Pathway

Bladder cancer arises when abnormal cells in the bladder proliferate uncontrollably, posing significant health challenges. However, recent advances in cancer research may provide new avenues for treatment.

Researchers at the Salk Institute have made significant progress in understanding the role of a protein known as PIN1 in the development of bladder cancer. Previous studies indicated that PIN1 plays a part in cancer progression, but its specific mechanisms remained elusive. The new findings reveal that PIN1 is a key contributor to bladder cancer by initiating the production of cholesterol, which is essential for cancer cell growth.

The research team mapped out the connection between PIN1 and cholesterol synthesis, leading to the development of a promising treatment approach. This regimen combines two medications: sulfopin, an experimental PIN1 inhibitor yet to be tested in humans, and simvastatin, a statin already approved for lowering cholesterol to mitigate cardiovascular risks.

The study was published in Cancer Discovery, a publication of the American Association for Cancer Research, on January 14, 2025.

According to Tony Hunter, a senior author on the study, this research represents a groundbreaking moment in identifying PIN1’s function in bladder cancer and understanding its mechanism in driving tumor growth. Given the burdens associated with bladder cancer, including high treatment costs and significant mortality rates, Hunter expressed optimism that targeting the cholesterol pathway with their therapeutic combination could lead to effective treatments in human trials once a PIN1 inhibitor gains clinical approval.

Bladder cancer is a prevalent form of cancer globally, ranking as the fourth most common type among men. It presents substantial public health concerns due to the financial and emotional toll associated with its treatment and often aggressive progression.

Hunter’s laboratory first identified PIN1 in 1996 while studying phosphorylation, a process whereby phosphate groups alter protein structure and function. The team established that PIN1 acts as an enzyme that interacts with specific phosphorylated proteins, fundamentally altering their configuration.

Alterations in phosphorylation, particularly involving serine and proline residues, can lead to cell proliferation and malignancy; disruptions in this signaling pathway are key contributors to various cancers. Although PIN1 was known to affect these processes, its precise role in bladder cancer remained under investigation.

To investigate further, the researchers compared normal bladder cells with cancerous ones, studying their behavior both in culture and in mouse models. They found elevated PIN1 expression in bladder cancer cells, particularly within the urothelium, the tissue lining the urinary bladder. Upon deactivating the PIN1 gene in cancer cells, the researchers observed a reduction in both the number of cancerous cells and their aggressive behavior.

The data suggested that PIN1 plays a crucial role in bladder cancer advancement but raised the question of how it exerts this effect. Investigating further revealed that the cholesterol synthesis pathway, regulated by a protein known as SREBP2, was significantly disrupted when PIN1 was absent. The bladder cancer cells exhibited markedly lower cholesterol levels without PIN1.

Xue Wang, the first author of the study, emphasized the necessity of cholesterol for cancer cells, stating that lower cholesterol levels correlated with diminished tumor growth. The researchers confirmed PIN1’s involvement in stimulating cholesterol synthesis alongside SREBP2, making it clear that inhibiting PIN1 could effectively curb tumor growth by restricting the cancer cells’ cholesterol supply.

To target PIN1’s role, the team considered not only inhibiting PIN1 directly but also blocking the cholesterol synthesis pathway it activates. Statins, a class of drugs frequently used to control cholesterol, served this purpose well by blocking HMGCR, an enzyme in that pathway. The researchers proposed a dual approach combining simvastatin with sulfopin to effectively reduce cholesterol production in bladder cancer cells.

The result of this combined treatment in mouse models showed a significant reduction in tumor growth and cancer cell proliferation, highlighting the synergy between the two drugs.

Hunter noted that while this research shines a light on PIN1’s function in bladder cancer, it could have broader implications for understanding PIN1’s role in other types of cancer. The existing use of statins for heart disease offers a potential pathway for repurposing these medications to enhance cancer treatment efficacy. Moving forward, the team plans to explore PIN1’s influence across different cancers, aiming to improve outcomes for a wide range of patients.

Other contributors to the study include Yuan Sui and Jill Meisenhelder from Salk Institute, Derrick Lee from UC San Diego, and Haibo Xu from Shenzhen University in China. The research received funding from the National Institutes of Health and a Pioneer Fund Postdoctoral Scholar Award.

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