A groundbreaking study has unveiled a protein that plays a pivotal role in the progression of bladder cancer by instigating the synthesis of cholesterol. Identified through extensive research using both mouse and bladder cancer cell models, this protein, known as PIN1, is crucial for cancer cell proliferation. Published in the journal Cancer Discovery, the study reveals how cholesterol serves as a fundamental building block for cell membranes, essential for the viability and growth of cancer cells. Researchers have found a promising combination therapy involving two drugs that disrupts the pathway leading to cancer cell creation and tumor growth.
Bladder cancer poses a significant challenge due to its recurrent nature, making it one of the more expensive cancers to treat. Patients typically require large surgeries and frequent check-ups to manage the disease. However, the recent findings bring hope for developing new treatment strategies, focusing on PIN1 as a target to impede bladder cancer progression.
“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,” – Tony Hunter, PhD
The combination therapy explored in the study comprises simvastatin and sulfopin. Simvastatin operates by blocking cholesterol synthesis both in cancer cells and the liver, while sulfopin specifically decreases cholesterol synthesis within tumor cells. By targeting PIN1, researchers aim to disrupt the cholesterol biosynthesis pathway that is vital for cancer cell survival.
“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,” – Tony Hunter, PhD
Bladder cancer patients face challenges due to the invasive nature of the disease and the need for regular medical attention. The study's insights into PIN1's role provide a potential avenue for more effective treatments. As Dr. Tony Hunter elaborates, cholesterol is indispensable for cell membranes and overall cell viability, with all body cells capable of producing it when local levels are low.
“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.” – Tony Hunter, PhD
Further research will focus on investigating PIN1's roles in various cell types within bladder cancer, such as fibroblasts, which contribute to tumor tissue architecture and cancer cell survival.
“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.” – Tony Hunter, PhD
The study also sets the stage for exploring other potential targets of PIN1 that may significantly impact bladder cancer cells, including additional elements of the cholesterol biosynthesis pathway.
“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,” – Tony Hunter, PhD
Dr. Jennifer Linehan underscores the complexity of cancer growth and formation, noting that many mechanisms remain poorly understood. She highlights the importance of enhancing the body’s immune system through approaches like immunotherapy while acknowledging that current treatments typically do not stop cancer growth directly.
“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.” – Jennifer Linehan, MD
“And so I think this is just one of (the tips) of the iceberg,” – Jennifer Linehan, MD
“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,” – Jennifer Linehan, MD
Dr. Hunter explains that PIN1's ability to alter protein structures is dependent on specific phosphorylation sites being recognized by this enzyme. This property makes PIN1 a conserved protein across many organisms, emphasizing its essential function.
“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,” – Tony Hunter, PhD
“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.” – Tony Hunter, PhD
Statins like simvastatin effectively lower circulating cholesterol by inhibiting its synthesis in the liver. Combining a PIN1 inhibitor with statins could therefore offer a viable treatment approach by reducing cholesterol production both in tumor cells and systemically.
“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.” – Tony Hunter, PhD
“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,” – Tony Hunter, PhD
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