To Be or Not to Be: Controlling Cellular Suicide
This is a representative 3-dimensional image of peripheral nuclear γ-H2AX distribution in response to TRAIL (γ-H2AX is red and the nuclear envelope is green).
When a cell is damaged and can no longer function properly, a complex series of molecular steps is triggered that allows it to die in a controlled manner. This cellular suicide is called programmed cell death, or apoptosis.
Apoptosis can be initiated in two ways. The first is by direct detection of damage within the cell. There is also an external pathway that is activated when certain signaling proteins bind to the cell’s surface and engage a death-inducing signaling complex inside the cell. TRAIL (TNF-related apoptosis-inducing ligand) is a protein that binds to specific cell surface receptors and activates apoptosis preferentially in cancer cells. The ability of TRAIL to induce death in cancer cells makes it an attractive therapy; in fact, there are several preclinical and clinical evaluations under way to assess the effect of TRAIL on a broad range of leukemias and solid malignancies.
In order to improve anticancer therapies using TRAIL, Stéphanie Solier, Pharm.D Ph.D., postdoctoral fellow in the Laboratory of Molecular Pharmacology headed by Dr. Yves Pommier at CCR, is attempting to elucidate the mechanism of action of TRAIL. She has investigated the complicated series of TRAIL-activated events that initiate apoptosis. Her paper, which describes the proteins involved and how they interact to trigger apoptosis, was highlighted on the cover of a recent issue of Molecular and Cellular Biology.
In normal cells, a signaling pathway is in place to activate apoptosis when DNA damage occurs. The researchers hypothesized that TRAIL could be utilizing the components of this DNA damage pathway to eliminate cancer cells. In order to test this hypothesis, the researchers used cultured cancer cells to monitor the effect of TRAIL on specific proteins.
Chk2, one of the proteins of the DNA damage response pathway, was indeed found to be activated by TRAIL. This protein has previously been identified in the regulation of checkpoints used by cells to determine whether DNA damage is serious enough to proceed with programmed cell death. In this study, Drs. Solier and Pommier showed that activation of Chk2 amplifies the signal through the cell death pathway and increases the number of cells that undergo TRAIL-mediated apoptosis. The authors also suggest that amplification of the Chk2 signal is important in making sure cells that have started to die due to exposure to TRAIL finish the process.
H2AX is another protein that is activated in normal cells in response to DNA damage. Following detection of DNA damage, H2AX reflects changes to the cell’s DNA that can be visualized using a specific antibody discovered by Dr. William Bonner in the Laboratory of Molecular Pharmacology, CCR. Upon activation of H2AX by TRAIL, changes were observed within the nucleus. However, these changes did not exhibit the same pattern as that observed in response to DNA damage. Those differences suggest that, although similar, the pathway utilized by TRAIL to trigger apoptosis is not exactly the same as the pathway used after DNA damage.
These results have many implications for the clinical treatment of cancer. The discovery that TRAIL utilizes segments of the DNA damage response pathway provides a rationale for combining TRAIL and DNA-damage agents for anticancer therapy. If tumor cells are first exposed to chemotherapeutic agents that induce DNA damage, they may become sensitized to TRAIL-mediated apoptosis due to preactivation of the Chk2 amplification loop. In support of this notion, some studies have detected a synergism between TRAIL and DNA-damaging therapies. Drs. Solier and Pommier’s results also suggest that it may be possible to predict the effectiveness of TRAIL therapy based on the level of Chk2 in tumors. It is also possible that activation of Chk2 in precancerous lesions or tumors may be able to prevent cancer development or delay its progression.Summary Posted: Thu, 01/01/2009
Mol Cell Biol. 2009 Jan;29(1):68-82. Epub 2008 Oct 27. PubMed Link