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J. Biol. Chem., Vol. 283, Issue 27, 99932, July 4, 2008

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Arresting Prostate Cancer

Many members of the Ras protein superfamily undergo a post-translational modification on their C terminus known as prenylation that is important for their overall stability and function. Considering the major role Ras proteins play in cancer, this chemical modification is also an ideal drug target. In this Paper of the Week, Mei Wang and colleagues evaluate the mechanism of one such drug called cysmethynil, a small molecule inhibitor of the enzyme isoprenylcysteine carboxylmethyltransferase (Icmt, which catalyzes the last step of the prenylation process). Using PC3 prostate cancer cells in both in vitro and in vivo models, they find that cysmethynil treatment results in an increased number of cells arrested in G₁ phase and increased cell death through autophagy; these two observances were likely induced by a decrease in mTOR signaling. This dual effect of growth arrest and cell death (through a non-apoptosis pathway) makes this small molecule inhibitor a candidate for a cancer therapeutic. As evidence of its potential, Wang and colleagues demonstrated that cysmethynil treatment could markedly reduce tumor size in mouse xenograft models.

Acridine orange labeling of PC3 cells reveals that cysmethynil treatment dramatically increases the number of acidic vesicles (orange-red), a marker for autophagy.

FOOTNOTES

See referenced article, J. Biol. Chem. 2008, 283, 18678-18684

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This Article Full Text (PDF) Author Profile Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Alert me to new issues of the journal Download to citation manager Related Collections Papers Of The Week Social Bookmarking                      What's this?