Doxorubicin Chemotherapy Involves Complex Gene Interactions

p21 functions as a regulator of cell cycle progression at G1 phase. The expression of p21 is controlled by the tumor suppressor protein p53. As a proliferation inhibitor, p21 plays an important role in preventing tumor development. This notion is supported by data indicating that p21-null mice are more prone to spontaneous and induced tumorigenesis, and p21 synergizes with other tumor suppressors to protect against tumor progression in mice. However, a number of recent studies have pointed out that in addition to being an inhibitor of cell proliferation, p21 acts as an inhibitor of apoptosis in a number of systems, and this may counteract its tumor-suppressive functions as a growth inhibitor.

Doxorubicin is known to interact with DNA by intercalation and inhibition of macromolecular biosynthesis. This inhibits the progression of the enzyme topoisomerase II, which unwinds DNA for transcription. Doxorubicin stabilizes the topoisomerase II complex after it has broken the DNA chain for replication, preventing the DNA double helix from being resealed and thereby stopping the process of replication. Doxorubicin works in combination with p53, one of the most protective anti-cancer proteins in the human body. However, doxorubicin also relies on p53-independent mechanisms to induce death in colon and breast cancer cells.

In the current study published in the November 1, 2007, issue of Cancer Research, investigators at the Virginia Commonwealth University (Richmond, USA) focused on the relationship between SphK2 and p21. They found that doxorubicin increased p21 activity via p53-dependent and p53-independent mechanisms. Down-regulation of endogenous SphK2 with small interfering RNA targeted to unique mRNA sequences decreased both basal and doxorubicin-induced expression of p21 without affecting increased expression of p53. Thus, human colon and breast cancer cells were killed more efficiently by doxorubicin when SphK2 was removed from the cells.

"Our findings suggest that SphK2 influences the balance between cytostasis, and apoptosis of human cancer cells,” said senior author Dr. Sarah Spiegel, professor of biochemistry and molecular biology at Virginia Commonwealth University. "Understanding how doxorubicin kills in a p53-independent manner is a major goal of cancer researchers because most cancer cells have mutated p53.”


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