A group of cancer biologists at the Salk Institute (USA) has discovered that the protein PIN1 is an important driver of bladder cancerwhile they have revealed that its elimination leads to a reduction in cholesterol and growth less uncontrolled tumor of this type of cancer.
In depth
After mapping the molecular pathway between PIN1 and cholesterol, the researchers developed a treatment regimen effective that largely stopped the tumor growth in their mouse model of cancer. The therapy consists of two drugs: a PIN1 inhibitor called sulfopin, an experimental drug not yet tested in humans, and simvastatin, a statin already used in humans for reduce cholesterol levels in order to reduce the risk of cardiovascular diseases.
The results have been published in the journal ‘Cancer Discovery’, from the American Association for Cancer Research. “We are excited to be the first to identify the role of PIN1 in bladder cancer and describe the mechanism used to boost tumor growth,” said the lead author Tony Hunterprofessor at the American Cancer Society and holder of the Renato Dulbecco Chair at Salk.
“Dice high costs, morbidity and mortality rates of bladder cancer, we are especially excited to discover that targeting the cholesterol pathway with this therapeutic combination was so effective in suppressing bladder tumor growth in miceand we hope to see this approach explored in a future clinical trial, once it is approved clinical use of a PIN1 inhibitor“he added.
More details
Bladder cancer is one of the most diagnosed worldwide and the fourth most common among men. It supposes a serious threat for public health, since most cases entail either expensive, lifelong treatment or rapid progression and mortality.
Hunter’s lab had discovered PIN1 in 1996 as part of his work on phosphorylation, a process in which phosphate molecules attach to proteins to change their structure and function. The laboratory demonstrated that PIN1 is an enzyme capable of recognizing a protein when a phosphate is added to the amino acid serine while it is next to the amino acid proline. PIN1 then changes the shape of that protein.
It is known that protein phosphorylation on serine residues close to prolines is a important mechanism signaling that controls cell proliferation and malignant transformation, and its deregulation is the cause of human cancers. PIN1 can address these phosphorylated areas and instigate structural and functional changes in the protein. However, it is not clear how this activity of PIN1 contributes to tumor formation or with what proteins it interacts in bladder cancer cells.
To take into account
In search of answersthe team compared normal human bladder cells with bladder cancer cells, in culture dishes and implanted in mice. First, they showed that PIN1 expression was higher in bladder cancer cells, specifically in the tissue layer specialized that lines the inside of the urinary tract, called urothelium. Next, they used genetic scissors to remove the PIN1 gene from the cancer cells. Without PIN1, They observed that fewer cancer cells developed and that those that developed migrated less aggressively in and out of the urothelium.
The researchers turned to cells that lacked PIN1 and checked whether other biological processes had been altered. Surprisingly, they discovered that one of the most affected pathways was cholesterol synthesis, mediated by a protein called SREBP2. Without PIN1, bladder cells contained much lower levels of cholesterol.
“Cancer cells need a lot of cholesterol to achieve its characteristic excessive growth. Our findings demonstrate that PIN1 plays an important role in cholesterol production, and its elimination leads to a reduction in cholesterol and, therefore, to a less uncontrolled tumor growth“said first author Xue Wang, a postdoctoral researcher in Hunter’s laboratory.
Through a series of experimentsthe researchers confirmed that PIN1 worked with the SREBP2 protein to stimulate cholesterol production. Deletion of PIN1 blocked fuel delivery to the cancer, but restoring it reversed the anticancer effects. Without intervention, high level of PIN1 in bladder cancer helps tumor growth and metastasis.
How to stop it
For researchers, an obvious answer to stopping PIN1 involves inhibit the protein itself, but they also consider that it is possible to inhibit an enzyme in the cholesterol pathway that PIN1 stimulates. One class of drugs, statins, is already widely used to control cholesterol levels. Statins work by blocking a protein in the cholesterol biosynthesis pathway called HMGCR..
The idea was to attack the cholesterol pathway from two angles by combining simvastatin, a widely prescribed statin, to block the HMGCRand sulfopine to deactivate PIN1 and prevent its activation of SREBP2, thus drastically reducing the ability of bladder cancer cells to produce cholesterol.
When the researchers they tried mice with bladder cancer tumors with the PIN1 inhibitor sulfopine and the HMGCR inhibitor simvastatin, they found that the combination suppressed cancer cell proliferation and tumor growth.
“The exciting thing about this discovery is that statins are already They are used in humans to prevent cardiovascular diseasesand our work suggests the possibility of using them in combination with other drugs to treat bladder cancer. And beyond this, we will continue studying “If PIN1 plays a similar role in other types of cancer, so hopefully our findings can improve lives regardless of cancer type,” Hunter concluded.
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