Researchers Examine the Link Between Proteasome Inhibitors and the FoxM1 Oncogene

Cancer researchers have defined the molecular basis for the link between the FoxM1 gene, one of the most overexpressed genes in human tumors, and the thiazole class of recently approved proteasome inhibitor chemotherapeutic drugs. FoxM1 is strongly upregulated in a variety of human solid tumors, while its expression is suppressed in nondividing cells.

Investigators at the University of Illinois (Chicago, USA) had previously shown that the thiazole antibiotics Siomycin A and thiostrepton inhibited FoxM1 and induced apoptosis in human cancer cells.

In a recent study published in the August 12, 2009, online edition of the journal PLoS ONE they extended this work and reported that Siomycin A and thiostrepton stabilized the expression of a variety of proteins, including some oncogene products, by inhibiting proteasome activity. This relationship was confirmed by findings that showed that well-known proteasome inhibitors such as MG115, MG132, and bortezomib inhibited FoxM1 transcriptional activity and FoxM1 expression. In addition, overexpression of FoxM1 specifically protected against apoptosis induced by the proteasome inhibitor bortezomib but not against apoptosis induced by doxorubicin, which does not function as a proteasome inhibitor.

"We found that these thiazole antibiotics actually stabilized other cancer-causing proteins," said senior author Dr. Andrei Gartel, associate professor of molecular genetics at the University of Illinois. "It is possible that by using thiazole antibiotics in combination with well-known proteasome inhibitors we may see a synergy that allows us to markedly reduce the dose of any one of these drugs and still effectively kill the cancer cells."

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