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Addition of Exogenous Nucleotides Reverses Oncogene-Induced Cellular Senescence

By LabMedica International staff writers
Posted on 17 Apr 2013
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Addition of exogenous nucleotides can reverse the condition known as oncogene-induced stable senescence-associated cell-growth arrest that was caused by a decrease in deoxyribonucleotide triphosphate (dNTP) levels due to the oncogene-induced repression of the enzyme ribonucleotide reductase subunit M2 (RRM2).

The tumor suppressing mechanism known as oncogene-induced cellular senescence results from DNA damage that might be triggered by depletion of DNA precursor molecules as well as by previously described phenomena such as oxidative stress and hyperreplication of genomic DNA.

Recently, it was shown that oncogene-induced senescence (OIS) occurs during the early stages of tumorigenesis. Senescent tumor cells are abundant within premalignant neoplastic lesions, whereas they are scarce in malignant tumors. This association of senescence with the premalignant stages of tumor progression opens the possibility of using senescence markers as diagnostic and prognostic tools. Moreover, some chemotherapeutic protocols induce senescence in tumor cells and, consequently, senescence markers could help to monitor treatment response.

Cellular senescence, a permanent cell cycle arrest, is considered a safeguard mechanism that may prevent aged or abnormal cells from further expansion. OIS is characterized by permanent growth arrest and the acquisition of a secretory, proinflammatory state. While OIS is now viewed as an important barrier to tumorigenesis, relatively little is known about the metabolic changes that accompany and therefore may contribute to OIS.

Investigators at the Wistar Institute (Philadelphia, PA, USA) reported in the April 4, 2013, online edition of the journal Cell Reports that decrease in dNTP levels caused by RRM2 suppression preceded the exit from the active cell cycle and coincided with DNA damage responses. Thus, down regulation of RRM2, an enzyme that catalyzes the formation of deoxyribonucleotides from ribonucleotides, was both necessary and sufficient for senescence. Suppression of nucleotide metabolism by RRM2 repression was also necessary for maintenance of the stable senescence-associated cell growth arrest. Addition of exogenous nucleosides was sufficient to overcome OIS-associated cell growth arrest.

RRM2 repression correlated with the senescence status in benign nevi and melanoma taken from human patients, and its knockdown initiated senescence of melanoma cells. In contrast, high RRM2 expression correlated with poor overall survival in patients with melanoma with oncogenic BRAF or NRAS genes.

"Oncogene-induced senescence is an automatic mechanism that arrests the growth of normal cells when an oncogene or cancer-causing gene is activated to prevent the progression of these cells into cancer," said senior author Dr. Rugang Zhang, an associate professor in the gene expression and regulation program at the Wistar Institute. "We identified how an oncogene can set senescence into motion by suppressing RRM2, an enzyme necessary for producing nucleotides."

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