Most targeted therapies for cancer are developed with the aim of shutting down the growth-promoting process, which runs amok. In particular, many of the targeted drugs used to treat cancer today block cancer-causing genes or proteins produced by oncogenes, which stimulate cancer cells to grow.
But another class of proteins important for the development of cancer has proved more difficult to manipulate: tumor-suppressive proteins. As their name suggests, these proteins normally act to inhibit abnormal cell growth. If they can be returned “on” with drugs, such an approach would represent another front in cancer medicine.
Researchers have now discovered a way to turn on one of the proteins that suppress tumors, called cancer, in both human cancer cells and mouse models. They also found a natural compound, currently sold as a dietary supplement, that could at least switch on in laboratory studies.
Rehab Yusin,” said Rehab Yesin, head of the Cancer Cell Biology Branch at NCI’s Division of Cancer Biology We’ve had a lot of success with attacking activator oncogene. “
Many cancer types, including breast and prostate cancers, often reduce their PTEN function as they increase, Drs. Yisson explained. As a result, proteins that are typically kept in check by PTEN (a signaling pathway) can become highly active and drive uncontrolled cell growth, she said.
Researchers have identified several cell-signaling pathways that regulate the behavior of PTEN. Dr. Pandolfi said that the paths discovered to date have not fulfilled the promise for treatment.
In search of an improved approach to reactivating PTEN in cancer cells, the study’s principal investigator, Yu-Ru Li, PhD, and his colleagues in the Pandolfi laboratory have taken 5-year studies for other proteins interacting with PTEN Started the search. They were looking for proteins flowing through cancer cells, which were physically bound to PTEN.
The team zeroed in on a protein,
WWP1, that was already known to be abundant in certain types of cancer. In a series of experiments, Drs. Li and his colleagues found that WWP1 prevents the molecules of PTEN from joining together in pairs and moving to the surface of cells. PTEN can perform its tumor-suppressive functions only when it is located in the surface area of cells.
Importantly, the team found that WWP1 is regulated by a well-known oncogene called MYC. MYC itself is a major driver of cancer, Drs. Explained Yison, but proved difficult to target safely.
When you knock it down or out, you affect other important cell functions that can cause unwanted side effects,” she said.
To see if WWP1 between MYP and PTEN might be a weak link to this pathway, the researchers destroyed the genes of WWP1 in mice that are genetically prone to develop prostate tumors.
They found that WWP1 deficient mice had much fewer and smaller prostate tumors than mice with the gene. When he analyzed tissue samples taken from mouse tumors, he found that more PTEN was able to make its way to the surface of cells in tumors of mice with WWP1 deletion.
In contrast, reduced PTEN went on the surface of cells in tumors of mice with normal WWP1. WWP1 looks like a very important oncogene, but it had no toxicity when knocked out,” he said.
After a safe on-switch, the
team looked for compounds that could potentially block WWP1. He used a computer to create 3D models of the structure of WWP1 and then fitted other molecules to it, such as a key that could fit in a lock.
The analysis predicted that a compound called indole-3-carbenol (I3C) could bind to WWP1 and prevent it from interacting with PTEN. I3C is found naturally in small amounts in some vegetables, including broccoli and Brussels sprouts. It is also sold over the counter as a dietary supplement.
When researchers treated too much WWP1-containing human cells with I3C, they noticed that PTEN began to accumulate on the cell’s surfaces, indicating that WWP1 was inhibited.
They then tested I3C in engineered mice to produce too much MYC. The compound given by the rat has developed much smaller tumors than those that did not. No side effects were observed with I3C at the dose required to produce this tumor-suppressive effect.
Dr. towards human trials . Lee said the researchers want to start a clinical trial of the I3C, although they acknowledge that doing so will take time and planning.