Refusal of suicide order: Why tumor cells become resistant

Jun 23, 2008

Cells with irreparable DNA damage normally induce programmed cell death, or apoptosis. However, this mechanism often fails in tumor cells so that transformed cells are able to multiply and spread throughout the body. Scientists at the German Cancer Research Center (Deutsches Krebsforschungszentrum, DKFZ) have now discovered a possible cause of this failure. Tumor cells simply degrade a protein that triggers apoptosis in the case of DNA damage. Blocking this protein degradation might set apoptosis back in operation and, thus, increase the effectiveness of radiotherapy or chemotherapy. The researchers have now published their results in Nature Cell Biology.

Proteins that trigger programmed cell death, or apoptosis, must be kept under careful control. After all, a cell should induce its own death only if its genetic material is damaged so severely that there is a danger of its transformation into a malignantly growing tumor cell. However, minor damages in the DNA can be corrected by the cell's special repair mechanisms – hence, no reason to commit suicide!

Among the proteins that trigger apoptosis after severe DNA damage is the HIPK2 molecule. Scientists in Dr. Thomas Hofmann's research group at the German Cancer Research Center (DKFZ) have now shown that although HIPK2 is continuously produced in healthy cells, it is instantly degraded again. An enzyme called Siah-1 attaches labels to HIPK2 marking it as "garbage". Thus, the cell prevents that apoptosis is induced "accidentally".

Slightly damaged cells enter a kind of alarm status: They block degradation of HIPK2 by Siah-1 for a short time. But as soon as the damage is repaired, the cell immediately resumes labeling HIPK2 as garbage and degrades the molecule. Only in severely damaged cells, such as by a broken DNA double strand, degradation of HIPK2 by the Siah-1 enzyme is blocked permanently. As a result, HIPK2 accumulates, apoptosis is triggered, and the cell commits suicide.

Researchers assume that this could be one of the reasons why radiation therapy or chemotherapy is sometimes ineffective. Both treatment methods cause severe damage to tumor cells, which eventually leads to programmed cell death. "If resistances occur, this is often caused by tumor cells 'refusing' to take the order to commit suicide," Thomas Hofmann explains.

To prevent HIPK2 degradation, Hoffmann and his colleagues conducted experiments in which they blocked the Siah-1 enzyme. As a result, HIPK2 was able to accumulate even in cells that were only slightly damaged, and apoptosis was induced. "Cancer medicine might be able to make use of our discovery," speculates Hofmann. "For example, we could use a Siah-1 blocker simultaneously with chemotherapy or radiotherapy to get the cells back into the apoptosis program."

Source: Helmholtz Association of German Research Centres

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gdpawel
not rated yet Jun 25, 2008
Why it is important to find whether tumor cells become resistant.

Apoptosis (cell death) is a genetically programmed cell death pathway which exists in all cells, which is supposed to cause them to commit suicide if they become functinally deranged, but doesn't function properly in cancer cells, allowing them to grow abnormally without committing suicide, which can be triggered to occur by "effective" anti-cancer drugs.

Functional profiling works on the biological principle that when a drug is effective, it will induce apoptosis in the cancer cell. If the cancer cell is resistant to a drug, apoptosis will not occur. Functional profiling for apoptosis will determine whether a drug kills the tumor.

All available bio-marker assays are able to report drug "resistance" information. Resistance implies that when a patient's cancer cells are exposed to a particular chemotherapy agent in the laboratory, the cancer cells will continue to live and grow. Some bio-marker assays are also able to report drug "sensitivity" information. Sensitivity implies that when a patient's cancer cells are treated with a particular chemotherapy agent in the laboratory, that agent will kill the cancer cells or inhibit their proliferation.

The goal of functional profiling assays is to determine the response of a patient's cancer cells to proposed chemotherapy agents. Knowing which chemotherapy agents the patient's cancer cells are resistant to is important. These options can be eliminated, thereby avoiding the toxicity of ineffective agents. Knowing which chemotherapy agents are most effective is important too. Choosing the most effective agent can help patients to avoid the physical, emotional, and financial costs of failed therapy and experience an increased quality of life.

In chemotherapy selection, gene and protein testing examine a single process within the cell or a relatively small number of processes. The aim of gene and protein testing is to tell if there is a theoretical predisposition to drug response. The goal is to look for patterns of normal and abnormal gene expression which could suggest that certain proteins might or might not be produced within a cell. Just because a gene is present, it does not mean that an associated protein has been produced.

Protein testing goes one step further by testing to see if the relevant protein actually has been produced. However, even protein testing cannot tell us if a protein is functional or how it will interact with other proteins in the presence of anti-cancer drugs (cytotoxic or targeted). Functional profiling tests not only for the presence of genes and proteins but also for their functionality, for their interaction with other genes, proteins, and processes occurring within the cell, and for their response to anti-cancer drugs.

Gene and protein tests cannot discriminate among the activities of different drugs within the same class. Instead, gene and protein tests assume that all drugs within a class will produce precisely the same effect, even though from clinical experience, this is not the case. Nor can gene and protein tests tell us anything about drug combinations.

Functional tumor cell profiling tests living cancer cells. It assesses the net result of all cellular processes, including interactions, occurring in real time when cancer cells actually are exposed to specific anti-cancer drugs. Functional tumor cell profiling can discriminate differing anti-tumor effects of different drugs within the same class. It can also identify synergies in drug combinations.

When considering a cancer drug which is believed to act only upon cancer cells that have a specific genetic defect, it is useful to know if a patient's cancer cells do or do not have precisely that defect. Although presence of a targeted defect does not necessarily mean that a drug will be effective, absence of the targeted defect may rule out use of the drug. Of course, this assumes that the mechanism of drug activity is known beyond any doubt, which is not always the case.

As you can see, just selecting the right test to perform in the right situation is a very important step on the road to personalizing cancer therapy.

Reference: Cell Function Analysis