New natural anti-cancer mechanism uncovered
A mechanism that can block most cancer types in cells has been identified by researchers at The Scripps Research Institute (TSRI), according to a new study in the journal Molecular Cell.
The cancer-blocking mechanism – coined "oncogene-induced senescence" – is commonly experienced when developing skin cancers turn into slow-growing moles instead.
Tumors that turn malignant often do so by jumping over this growth hurdle, and researchers have long been interested in finding out exactly how that process works.
"We have known about some of the molecular signals that mediate this senescence response, but we've needed to understand the signaling pathway in much more detail," said Peiqing Sun, associate professor in TSRI's Department of Cell and Molecular Biology.
In the new study, published recently in the journal Molecular Cell, Sun and his colleagues describe the cascading interactions of three enzymes that are necessary to initiate a common type of oncogene-induced senescence.
An oncogene is a gene that has the potential to cause cancer. In tumor cells, they are often mutated or show up at elevated levels, which can help turn a normal cell into a tumor cell. However, many abnormal cells can usually cause those cells to survive and proliferate instead.
Most oncogenes require an additional step, such as mutations in another gene, or environmental factors, like a viral infection, to cause cancer. Since the 1970s, dozens of oncogenes have been identified in human cancer. Many cancer drugs target the proteins encoded by oncogenes.
In 2007, Sun and other researchers showed that an enzyme called p38 plays a role in the process by activating another enzyme, called PRAK.
For this new study, however, Sun and his colleagues, including research assistant Hui Zheng, set out to learn more about PRAK's role in this process.
Zheng began the investigation by searching for binding partners of PRAK.
With a series of protein-interaction assays he isolated an enzyme called Tip60, which binds tightly to PRAK. Further tests indicated that Tip60 does, in fact, lie within the senescence-inducing signaling process because senescence fails to occur when Tip60 is absent.
At first, Zheng and Sun suspected that PRAK would interact with Tip60 by activating it.
But what they found was just the opposite was true: Tip60 actually activates PRAK.
"Our tests showed that Tip60 binds to PRAK and acetylates it at a certain location, which helps activate PRAK," said Zheng.
Sun and his laboratory have shown previously that PRAK, when activated, goes on to activate the key tumor-suppressor protein p53, which exerts more direct control over a cell's growth machinery.
Sun and his team have been looking for ways to force the activation of the senescence response in cancer cells, as a potential cancer-drug strategy.
"Finding these details of the early part of the signaling cascade helps us understand better what we need to target," he said.
SOURCES: 1. The Scripps Research Institute (TSRI), “New details of natural anticancer mechanism uncovered”, June 11, 2013. 2. Molecular Cell, “A Posttranslational Modification Cascade Involving p38, Tip60, and PRAK Mediates Oncogene-Induced Senescence”, June 6, 2013 (Vol. 50, Issue 5, pp. 699-710).