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Why a signaling molecule suppresses cancer cell growth only if it’s produced in the nucleus

Taha Merghoub

A study co-led by Ludwig Weill Cornell’s (formerly MSK) Taha Merghoub uncovered how a signaling molecule known as cyclic AMP (cAMP) either stimulates or suppresses tumor growth depending on where it is produced within the cell. To do that, the researchers developed a new, tunable method to target cAMP signaling to distinct compartments in cancer cells in culture and in mice. Taha and his colleagues reported in a September issue of Cell Reports that cAMP signaling generated distinct gene expression profiles depending on its intracellular location. They found that cAMP production in the nucleus suppresses tumor growth in a wide variety of cancers. It does so, they showed, through a previously unknown effect it has on the Hippo signaling pathway, which drives cancer cell proliferation and invasion: cAMP inhibits a key effector protein of that pathway known as YAP. The findings suggest that pharmacologically boosting cAMP levels in the nucleus could represent a new cancer therapy. One approach to doing so might be to target an enzyme known as phosphodiesterase, which breaks down cAMP, perhaps using one of several candidate drugs that are already in clinical use. The trick, of course, would be finding—or making—one that works mainly in the cell’s nucleus.

A nuclear cAMP microdomain suppresses tumor growth by Hippo pathway inactivation
Cell Reports, 2022 September 27

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