A groundbreaking study has identified a protein that plays a crucial role in the progression of bladder cancer by triggering cholesterol synthesis. The protein, known as PIN1, was discovered by Tony Hunter, PhD, and is believed to drive cancer growth by increasing cholesterol levels in both mouse and human bladder cancer cell models. Researchers have found that a combination therapy using two drugs, simvastatin and sulfopin, effectively disrupts the cancer-promoting pathway initiated by PIN1, offering potential new avenues for treatment.
Bladder cancer is notorious for its recurrence and the substantial surgical interventions required to treat invasive forms of the disease. It ranks among the more expensive cancers to manage due to this tendency to recur. The recent study, published in the journal Cancer Discovery, highlights cholesterol as a key component in cell membrane construction and essential for cell viability. By targeting the cholesterol biosynthesis pathway, the study suggests a promising approach to combatting 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,” – Hunter
Hunter's research demonstrates that PIN1 not only promotes cell proliferation but also enables tumor cells to migrate and invade surrounding tissues. This discovery sheds light on why bladder cancer cells thrive and spread, providing new insights into potential treatment strategies.
“PIN1 is also needed for the tumor cells to migrate and invade the surrounding tissue to form a tumor.” – Hunter
The study reveals that simvastatin blocks cholesterol production both in cancer cells and the liver, while sulfopin specifically targets tumor cells to reduce cholesterol synthesis. Together, these drugs significantly lower cholesterol levels in bladder cancer tissue, impeding 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
Hunter emphasizes that PIN1 is an enzyme capable of altering protein structures, which can either enhance or diminish their activity. This characteristic of PIN1 makes it a critical player in multiple intracellular cancer pathways.
“PIN1 is an enzyme that is able to alter the local structure of a protein either increasing or decreasing its activity, but only if a phosphate has been attached to that protein in a particular place first, which is then recognized by PIN1,” – Hunter
The high conservation of PIN1 across various organisms indicates its essential function in cellular processes. In humans, PIN1 influences many proteins, tweaking their structures once activated by a kinase enzyme. It remains present at elevated levels in numerous cancers, including breast cancer.
“PIN1 is present in all organisms whose cells have nuclei, from yeast to humans, and its high degree of conservation during evolution indicates it has an important function.” – Hunter
Jennifer Linehan, MD, a board-certified urologist who reviewed the study, finds the research promising. She acknowledges the challenges in understanding why and how cancer grows and emphasizes the importance of discovering new treatment mechanisms.
“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
Linehan notes that enhancing the body's own immune system through immunotherapy is one approach currently used. However, there are few treatments available that directly stop cancer growth. She believes that targeting pathways like cholesterol biosynthesis could represent a significant step forward.
“Some of it is enhancing the body’s own immune system, like immunotherapy … There’s nothing really out there that we’re using that’s going to stop the growth, and so I think that that’s why this is so interesting because that kind of mechanism of treatment is one, not commonly discovered, and two, not commonly pursued,” – Linehan
Hunter and his team plan further research on PIN1's role in other cell types within bladder cancer, such as fibroblasts. They aim to explore additional targets for PIN1 that may be significant in bladder cancer cells.
“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
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