Parvoviruses are a class of viruses that normally infect rodents; in humans, they do not cause any disease symptoms. However, they are able to infect and kill cancer cells. The details behind this biological selectivity on the part of the viruses have not been understood until now. "Since the viruses might soon play a role in cancer medicine, it is important to know why they replicate exclusively in tumor cells in humans," says virologist Dr. Jürg Nüesch from the German Cancer Research Center (Deutsches Krebsforschungszentrum, DKFZ).
In order to complete their life cycle within the cell and to produce the next generation of viruses, the viruses depend on the activity of a specific cellular enzyme called PDK1 kinase. This kinase acts like a main switch for numerous cellular functions. Normally, it is activated from the outside by growth factors that attach to the cell.
Nüesch and his colleagues, Séverine Bär and Jean Rommelaere, have now discovered that in the cells of mice, which are natural hosts for parvovirus H1, the virus is able to activate PDK1 via an internal pathway that is independent of growth factors. An enzyme complex called PKCη/Rdx is involved in this process. This complex transfers a phosphate group to a specific protein building block of PDK1, leading to its activation.
In normal human cells, however, where the virus cannot replicate, it is unable to activate PDK1 using this alternative pathway. When the researchers equipped these normal cells in the Petri dish with permanently activated PDK1, the virus was successfully able to infect the cells and replicate inside of them.
The situation is different in cancer cells, especially in glioblastoma - the most malignant kind of brain tumor. Nüesch and his colleagues examined 70 glioblastoma tissue samples and discovered that in 36 percent of these samples, PDK1 was already phosphorylated from the start and, therefore, permanently activated.
"For the cancer cells, permanent activation of PDK1 is biologically useful because it allows them to be independent of growth factors," Nüesch explains. "The parvoviruses, in turn, exploit this for their own purposes. Thus, we have found, for the first time, a molecular cause for the virus's natural selectivity for cancer cells. Additionally, in PDK1 phosphorylation we have discovered a biomarker that enables us to predict whether therapy with parvoviruses can be effective in a particular tumor."
In the treatment of brain cancer, one approach currently being tested is the use of substances that block growth factor receptors on the cell surface. The detection of PDK1 phosphorylation also has predictive value in this regard. If PDK1 is activated via the alternative pathway, then the cancer cell is independent of growth factors; therefore, blocking them would not help the patient.
Under the leadership of Jean Rommelaere, scientists at the DKFZ have been studying parvoviruses since 1992. Their goal is to develop a viral therapy to attack glioblastoma. At Heidelberg Neurosurgical University Hospital, a preliminary clinical trial has been ongoing since 2011, where the safety of treatment with H1 virus is currently being evaluated.
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Séverine Bär, Jean Rommelaere, and Jürg P.F. Nüesch: PKCη/Rdx-driven Phosphorylation of PDK1: A Novel Mechanism Promoting Cancer Cell Survival and Permissiveness for Parvovirus-induced Lysis. PLOS Pathogens 2015, DOI: 10.1371/journal.ppat.1004703
The German Cancer Research Center (Deutsches Krebsforschungszentrum, DKFZ) with its more than 3,000 employees is the largest biomedical research institute in Germany. At DKFZ, more than 1,000 scientists investigate how cancer develops, identify cancer risk factors and endeavor to find new strategies to prevent people from getting cancer. They develop novel approaches to make tumor diagnosis more precise and treatment of cancer patients more successful. The staff of the Cancer Information Service (KID) offers information about the widespread disease of cancer for patients, their families, and the general public. Jointly with Heidelberg University Hospital, DKFZ has established the National Center for Tumor Diseases (NCT) Heidelberg, where promising approaches from cancer research are translated into the clinic. In the German Consortium for Translational Cancer Research (DKTK), one of six German Centers for Health Research, DKFZ maintains translational centers at seven university partnering sites. Combining excellent university hospitals with high-profile research at a Helmholtz Center is an important contribution to improving the chances of cancer patients. DKFZ is a member of the Helmholtz Association of National Research Centers, with ninety percent of its funding coming from the German Federal Ministry of Education and Research and the remaining ten percent from the State of Baden-Württemberg.
Journal
PLoS Pathogens