Sylvester Comprehensive Cancer Center

Sylvester Researcher Uncovers New Pathway Regulating Cancer Inhibitor

09.26.2008

In the battle against breast cancer, a top researcher at the Braman Family Breast Cancer Institute at Sylvester Comprehensive Cancer Center at the University of Miami Miller School of Medicine has uncovered a new pathway for p27 which regulates cell growth. The finding, published in the June 20th issue of Molecular Cell, provides a new rationale for targeting two different growth pathways to more effectively stop cancer growth.

Joyce M. Slingerland, M.D., Ph.D., director of the Braman Family Breast Cancer Institute at Sylvester, led the research which closely examined the cell-signaling protein, mTOR (mammalian target of rapamycin), and its effects on p27. Her team included Feng Hong, M.D., Ph.D., post doctoral associate, and Michelle D. Larrea, Ph.D., research associate, plus two scientists from Brigham and Women’s Hospital at Harvard Medical School. “This study gives scientists a new rationale,” says Slingerland, “for combining anti-cancer drugs that specifically target this pathway.”

The molecule p27 is a natural growth inhibitor that acts in the cell nucleus, regulating the timing of cell division. It is a ‘brakes molecule.’ “Cancer cells have a way of disturbing the normal function of p27,” says Slingerland. One way is to degrade this brake molecule too quickly, keeping it from working. In a paper published last year, (Cell, January 2007) Slingerland and her team showed how the Src oncogene tagged p27 to signal the protein degradation machinery.

Another way to interfere with p27’s function is to keep it locked in the wrong place in the cell. Many cancers show aberrant activation of the PI3Kinase and mTOR growth pathway signaling systems. Slingerland’s group found that activation of these pathways causes p27 to stay in the cytoplasm, away from its normal site of action, the nucleus. Keeping p27 in the cytoplasm blocks the molecule’s normal growth inhibiting function and also promotes cell motility. “When a cell acquires greater motility,” says Slingerland, “it can become more invasive and might metastasize.”

In a majority of cancers, the PI3Kinase pathway is activated, setting off a chain of events. PI3K then leads to the phosphorylation of Akt, which in turn phosphorylates p27, keeping it in the cytoplasm. Part of that growth signaling path includes mTOR, a protein kinase that regulates cell growth. In this study, Slingerland’s team learned that mTOR binds to SGK, which can phosphorylate p27 in the same way as Akt.

Thus, mTOR/SGK1 activation contributes to keeping p27 in the cytoplasm, away from its normal site of action. Scientists have known for many years that mTOR was a key regulator of new protein synthesis. Slingerland’s group uncovered a new way in which it regulates the cell cycle. “We identified a new pathway downstream of mTOR that contributes to inactivating the p27 molecule,” she says.

Slingerland describes P27 as a ‘Jekyll and Hyde’ molecule. “In its Jekyll form, p27 is a growth inhibitor. In its Hyde form, p27 is out there in the cytoplasm causing cells to become more motile and promoting metastasis.” The Sylvester scientist and physician says “what we found here is a new way, via SGK and mTOR, which causes p27 to go out into the cytoplasm.”

A handful of drug companies are developing mTOR inhibitors, such as RAD-001 (Novartis), and CCI-779 (Wyeth) and efforts to develop drugs that target PI3K and Akt are also underway. This breakthrough discovery indicates that anti-cancer strategies that target both Akt and mTOR or SGK will more effectively impair cancer growth than drugs that target each kinase alone.

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