On the Road to Rational Cancer Therapy

The p53 protein is an important human defense against cancer, protecting against cancer at least three ways:

1. It can activate DNA repair proteins when DNA has sustained damage.
2. It can also hold the cell cycle at the G₁/S regulation point on DNA damage recognition (if it holds the cell here for long enough, the DNA repair proteins will have time to fix the damage and the cell will be allowed to continue the cell cycle.)
3. It can initiate apoptosis, the programmed cell death, if the DNA damage proves to be irreparable.

Source

Researchers at the UPenn Schools of Medicine and Veterinary Medicine plan to pre-screen patients' tumours for p53, to verify if treatment with proteasome inhibitors would be effective for that tumour.

They propose to test for p53, a well-known tumor-suppressor protein that is broken down by cellular machinery called proteasomes. This study appears online in the journal Blood, in advance of print publication in June 2007.

In cancer patients whose tumors do not produce p53, proteasome inhibitors might be ineffective. This patient group could be spared unnecessary treatment with possible harmful side effects. On the other hand, proteasome inhibitors are highly effective against lymphomas that do have the ability to produce p53.

“Proteasomes resemble paper shredders – they break down proteins such as p53 into smaller pieces,” says senior author Andrei Thomas-Tikhonenko, PhD, Associate Professor of Pathology. “A proteosome inhibitor effectively jams the shredder so that p53 is not immediately broken down.”

In this study, the research team used a mutant strain of mice in which p53 activity can be switched on and off. “In principle, tumors in these mice could be obliterated by turning p53 back on,” says Thomas-Tikhonenko. “The problem was that a protein called MDM2 sent p53 into the teeth of the proteasome shredder.” The proteasome inhibitor bortezomib (Velcade®) causes this jamming process and restores p53 function. However, if p53 was inactivated in the mice, bortezomib treatment failed to kill tumors. Similar effects were seen with cell lines derived from human Burkitt’s lymphomas. When implanted into mice, these lymphoma cells were highly sensitive to the proteasome inhibitor, but as soon as p53 was removed, the inhibitor had no effect.

“These findings have important implications for clinical practice,” Thomas-Tikhonenko adds.

Source

Proteasomes degrade short-lived proteins as a normal housekeeping function. Eventually, more selective ways of increasing the action of p53 in tumour cells will be developed, but as a stop-gap measure on the road to rational cancer therapy, proteasome inhibitors will be a useful tool.