Department of Molecular Biology Lerner Research Institute Cleveland Clinic Foundation Cleveland, Ohio, USA gudkov@ccf.org
Selenium-containing compounds are in phase 2 and 3 clinical trials for prostate cancer prevention, although it is unclear how they work. A study suggests that selenium can facilitate DNA repair by activating the p53 tumor suppressor in an unusual way.
Cancer prevention is an ultimate goal of oncology. This is especially desirable as even successful cancer treatment is a painful and unpleasant experience frequently followed by severe disabilities. Cancer prevention so far has been largely limited to prophylactic measures aimed at avoiding cancer-provoking habits (such as smoking and drinking) or reducing exposure to environmental or dietary carcinogens (such as asbestos and charred foods). Rare cancer-preventive compounds that have made it all the way to clinical trials have come from empirical observation rather than laboratory research. One of the most well known among these preventatives is selenium. Selenium's cancer-preventive properties have been appreciated for more than 20 years with no clue about the mechanism of its anti-cancer activity1. In a recent Proceedings of the National Academy of Science USA, Seo et al.2 show that the form of selenium in food can modify the tumor suppressor p53. This modification activates an unusual protective function for p53 and may be central to selenium's anti-cancer powers.
Because cancer originates from a combination of mutations accumulated by somatic cells, any natural mechanism securing genetic stability should contribute to cancer prevention3. Furthermore, failure of natural mechanisms insuring accuracy of DNA repair increases the risk of carcinogenesis. One of the most important mechanisms controlling genetic stability is built around p53, known as a 'guardian of the genome'4. Under normal growth conditions, this protein is rapidly degraded. When the cell passes through a severe stress, broken DNA activates several kinases that phosphorylate and stabilize p53. As a result, p53 is rapidly accumulated in the nucleus where it acts as a transcription factor, changing expression of a set of genes that send cells down a path either to growth arrest or cell suicide. The final outcome depends on the severity of damage and the cell type: cells from tissues with high turnover rate, such as bone marrow or digestive tract epithelia, tend to apoptose whereas cells of the connective tissue, fibroblasts, frequently end up with irreversible growth arrest. However, either mechanism restricts propagation of damaged cells, thus reducing the risk of accumulating potentially cancerous cells. Thus, p53 is believed to maintain genetic stability through self-elimination of cells with damaged DNA.
Not surprisingly, this mechanism of self-control is frequently inactivated in tumors that acquire mutations in the genes encoding p53 itself or in other components of its signaling pathway5. This broadly accepted paradigm of p53 function favors development of therapeutic approaches involving restoration of the lost p53 function in the tumors, leading to growth inhibition of cancer cells. However, it leaves no room for cancer prevention through activation of p53, as increased activity of this protein should be detrimental for growth of normal tissues. Notably, the study by Seo et al. suggests a revision of this traditional thinking. The report indicates that maintenance of genomic stability by p53 can be separated from its growth suppressive or pro-apoptotic functions and may involve direct activation of DNA-repair machinery. This separation is achieved by p53 interaction with a selenium-containing compound, thus providing a possible mechanism for the long-known cancer preventive function of selenium.
Seo et al. found that incubation with selenomethionine (SeMet), the major source of selenium in our diet, results in an unusual activation of p53 in cultured cells: a reduction of two specific cysteine residues within p53 leads to a conformational shift and induction of p53 DNA-binding activity. The effect of SeMet on p53 is not due to a direct interaction with p53 nor is it due to DNA damage. It requires the cellular protein Ref1, a known redox factor that was previously shown to physically interact with p53 (ref. 4); inactivation of this protein blocks p53 modification by the selenium-containing compound. However, the most unusual property of the modified p53 is that p53 becomes capable of activating DNA-repair machinery without affecting cell growth. As a result, cells with wild-type p53, but not cells deficient in p53, can tolerate higher doses of ultraviolet irradiation if grown in the presence of SeMet. Hence, p53 can contribute to genomic stability not only by eliminating damaged cells from the population, but also through directly activating a DNA-repair system.
p53-mediated activation of DNA repair has been noted before4, along with a relationship between cancer preventive activity and p53 gene dose. The real news of the Seo et al. study is that p53 can induce DNA repair through a specific modification distinct from its DNA damage−responsive form and that SeMet induces this alternative modification. These observations provide a plausible explanation for the cancer-preventive activity of SeMet. SeMet likely works by causing permanent p53-mediated activation of DNA repair (as long as the compound is present), which helps to reduce the accumulation of mutations in somatic cells.
It would be somewhat premature to generalize this model before the described phenomenon is confirmed in different cell types and tested in vivo. However, if proven right, it would provide a mechanistic explanation for the activity of one of the most promising cancer preventive agents.
p53 has long been considered a prime target for therapeutic modulation6. Small p53-directed molecules with anti-cancer activity have been recently isolated. These include p53 inhibitors, capable of reducing the side effects of cancer treatment7. Other compounds can restore the wild-type conformation of p53 in tumors8,
9. The data of Seo et al. raise the intriguing possibility of the development of a different functional class of p53-targeting agents: cancer-preventive pharmaceuticals that, like SeMet, convert p53 into an active healing, rather than a traditional killing form.
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