Cross section of a human liver, taken at autopsy examination, showing multiple large pale tumor deposits; the tumor is an adenocarcinoma Wikicommons public domain; derived from a primary lesion in the body of the pancreas.
A new study from the University of North Carolina has found a possible therapeutic target for pancreatic cancer, one of the most lethal cancers. The results, published in the June issue of the journal Cancer Discovery, reveal a protein which helps these cancer cells avoid death and continue to multiply.
Our cells receive a variety of signals all the time. When a signal arrives, specific receptors on the cell membrane are activated and turn other molecules (proteins) on inside the cells. These active proteins will, in turn, activate further proteins, thus creating a chain of reactions that scientists call “protein pathway”.
The KRAS pathway, named after KRAS (Kirsten rat sarcoma viral oncogene), the protein at the beginning of the pathway, sends signals at certain proteins called transcription factors, which activate genes in the nucleus. All cells have KRAS and it is important in a variety of functions. But one single mutation in its gene results in a hyper active protein and it is very common in tumors of cells of the pancreas (pancreatic cancer).
This mutant, superactive KRAS pathway continuously sends signals to the transcription factor NF-κB and orders it to switch-on several genes involved in cell proliferation, survival and invasion. This is exactly what a cancer cell needs to keep multiplying, protect itself from death and later invade other tissues.
For these reasons, researchers have tried to tackle the function of KRAS in cancers. But this did not work well because KRAS is at the top of the pathway; therefore, a whole set of important reactions are also interrupted, in addition to the NF-κB. And since the healthy cells also contain KRAS, toxicity becomes an issue. Therefore, scientists want to identify other proteins that function further down in the KRAS pathway and use them as therapeutic targets without blocking the entire chain of reactions.
Working towards this direction, Deepali Bang, a graduate student in the laboratory of Albert Baldwin, and her colleagues, hypothesized that the glycogen synthase kinase 3 (GSK-3) functions to promote the hyperactivity of NF-κB via KRAS.
The research team used pancreatic cancer cell models with mutated KRAS and added a drug which inhibits GSK-3. They found that cancer cells were not happy and died. That was because GSK-3 has an important role in controlling NF-κB. Their results showed that mutant KRAS switches-on GSK-3, which then helps other proteins become more stable and keep the NF-κB always active.
“Our data suggest that GSK-3 is really an oncoprotein and that KRAS utilizes GSK-3 to activate NF-kappa B pathways, …thus making it a viable therapeutic target. We are conducting further pharmacologic studies,” said Baldwin.
Pancreatic cancer is one of the most aggressive cancers. In 2013, approximately 45,000 new cases in U.S. are estimated with more than 38,000 deaths. It is very rare that someone with pancreatic cancer will survive more than 5 years once diagnosed. Since GSK-3 is minimally active in healthy cells and, therefore, they might not need it as much as cancers do, it can be a very good therapeutic target with no or small side effects. How exactly GSK-3 stabilizes these proteins is yet unknown and might be the key to understand this process. However, this discovery is very important for cancer therapy in general, as many cancer types have mutated KRAS.
