Researchers at the Salk Institute for Biological Studies in California have identified a promising combination therapy that could revolutionize the treatment of bladder cancer. The study, published in the journal Cancer Discovery, highlights the role of cholesterol in cancer cell proliferation and introduces two drugs that disrupt this process. The combination of simvastatin and sulfopin shows potential in suppressing tumor growth by targeting the synthesis of cholesterol within cancer cells.
Bladder cancer, known for its high recurrence and costly treatment, demands innovative approaches. The study underscores the importance of finding new treatment methods, as existing options often require large surgeries and repeated interventions. Researchers focused on a protein called PIN1, which drives bladder cancer by triggering cholesterol synthesis. Through both mouse and bladder cancer cell models, they found that cholesterol is a critical component in cancer cell viability.
“In bladder cancer, our work shows that PIN1 is important for bladder cancer cells to proliferate and grow, and to prevent the tumor cells from committing suicide by a process known as apoptosis,” said Dr. Tony Hunter, the senior author of the study.
PIN1 plays a multifaceted role in cancer progression. Dr. Hunter elaborated on its functions, emphasizing that it is essential for tumor cells to migrate and invade surrounding tissues. The research revealed that PIN1 alters the local structure of proteins, influencing their activity particularly when a phosphate group is attached. This process was observed to be prevalent in many cancers, including breast cancer.
To address this, the team explored the use of simvastatin and sulfopin. Simvastatin, a drug commonly used to lower cholesterol levels, acts on both liver-produced and cancer cell-derived cholesterol. Sulfopin, on the other hand, decreases cholesterol synthesis directly within tumor cells. Together, these drugs significantly reduce cholesterol levels in bladder cancer tissues.
“Statins block the synthesis of cholesterol in (the) liver to lower the level of circulating cholesterol, which is what is measured when you have a blood draw for a cholesterol test. So simvastatin is acting in the mouse to block both cholesterol made by the cancer cells themselves and by the liver, and sulfopin is working in the tumor cells to decrease synthesis of cholesterol. Together, the combination results in much lower levels of cholesterol in the bladder cancer tissue, thus reducing tumor growth,” Dr. Hunter explained.
The findings suggest that cholesterol is more than just a dietary concern; it is a building block for cell membranes and vital for cell viability. The study indicates that controlling cholesterol levels can impede tumor growth, offering a novel angle for cancer treatment.
“The cholesterol we mention is the same chemical as the cholesterol that we get through our diet, and also the cholesterol that is made in the liver and enters our circulation,” Dr. Hunter noted.
“Cholesterol is a key building block of cell membranes and is essential for cell viability. All cells in the body can make cholesterol for their own use when the local levels of cholesterol are low, and this is the process that PIN1 is driving in the bladder cancer cells.”
The implications of this research extend beyond bladder cancer. Dr. Hunter's team plans to investigate PIN1's role in other cell types within bladder cancer and explore additional targets within the cholesterol biosynthesis pathway.
“We plan to follow up on our findings to study the roles of PIN1 in other cell types in bladder cancer such as fibroblasts, which contribute to the tumor tissue stromal architecture and to the survival and proliferation of the tumor cells. We will also survey for other targets for PIN1 that might be important in bladder cancer cells, including other side-products of the cholesterol biosynthesis pathway,” said Dr. Hunter.
This study opens new avenues for cancer treatment by presenting a method that targets cancer's metabolic pathways rather than its genetic mutations alone. Dr. William Linehan commented on the broader impact of these findings.
“There is so much about why cancer grows, how cancer forms, that we clearly don’t understand. There [are] definitely actors at play that are dictating the growth, dictating the invasiveness, that we don’t understand. And so I think this is just one of (the tips) of the iceberg,” said Dr. Linehan.
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