A groundbreaking study, recently published in the journal Cancer Discovery, has identified a protein that plays a pivotal role in driving bladder cancer by triggering cholesterol synthesis. Conducted by researchers at the Salk Institute for Biological Studies in California, the study reveals that a combination therapy of two drugs, simvastatin and sulfopin, can disrupt the cholesterol synthesis pathway, effectively suppressing cancer cell creation and tumor growth.
The research utilized both mouse and bladder cancer cell models to investigate the effects of this combination therapy. The study's lead author, Tony Hunter, PhD, emphasized the significance of their findings, highlighting the potential of targeting the cholesterol synthesis pathway as a promising approach to treating bladder cancer.
“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 Hunter.
Bladder cancer remains one of the more expensive cancers to treat due to its recurrent nature and often requires invasive surgery. Researchers are actively seeking new ways to manage and treat this type of cancer effectively. By focusing on the protein PIN1, which is intricately involved in cholesterol synthesis, they have uncovered a potential therapeutic target.
“PIN1 is also needed for the tumor cells to migrate and invade the surrounding tissue to form a tumor,” Hunter explained.
Cholesterol serves as a crucial building block for cell membranes and is vital for cell viability. In human cells, PIN1 acts on various target proteins, adjusting their structures once a phosphate signal has been introduced by a kinase enzyme. This enzyme's activity has been observed at elevated levels in several cancers, such as breast cancer, where it activates proteins in pathways that drive cancer or deactivates proteins that typically inhibit excessive growth.
“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,” Hunter noted.
The study's innovative approach combines simvastatin, a drug primarily known for lowering cholesterol levels by blocking its synthesis in the liver, with sulfopin, which targets tumor cells to decrease their cholesterol synthesis. This combination results in significantly lower cholesterol levels within bladder cancer tissues, thereby reducing tumor growth.
“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,” Hunter elaborated.
Dr. Jennifer Linehan, a board-certified urologist and associate professor of urology and urologic oncology, expressed optimism about the study's findings. She emphasized the importance of understanding the underlying mechanisms that dictate cancer growth and invasiveness.
“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,” Linehan commented.
The researchers plan to extend their investigation by exploring other targets for PIN1 that may be critical in bladder cancer cells. These targets include other side-products of the cholesterol biosynthesis pathway and roles of PIN1 in different cell types such as fibroblasts, which contribute to tumor tissue structure and support tumor cell survival and proliferation.
“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,” Hunter stated.
The study suggests that a PIN1 inhibitor drug paired with a statin could offer a viable treatment option by reducing cholesterol production within tumor cells and decreasing circulating cholesterol produced by the liver.
“Therefore, a PIN1 inhibitor drug given in combination with a statin to reduce cholesterol production in the tumor cells and decrease circulating cholesterol produced by the liver might be a viable treatment option in some other cases,” said Hunter.
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