Sci. Aging Knowl. Environ., 24 May 2006
Vol. 2006, Issue 9, p. nf15
[DOI: 10.1126/sageke.2006.9.nf15]


Shortcut to Death

Stubby protein spurs cancer cells to eat themselves

Mitch Leslie

Like shipwrecked sailors, famished cells sometimes turn to cannibalism. Rather than eating their mateys, though, they devour their own contents. A previously overlooked protein boosts cancer cells' appetite, triggering them to commit suicide, according to a new study. The research solidifies the controversial connection between self-consumption and cancer.

Cells can survive hard times by recycling their innards, a process called autophagy (see Cuervo Perspective). Membrane-enclosed bags termed autophagosomes scoop up some of the cell's cytoplasm. They then carry their contents to organelles called lysosomes for digestion. Autophagy slacks off as we get older, and the slowdown might contribute to aging by allowing oxidant-damaged proteins to build up (see "Picky Eater"). Self-eating might also break down in illnesses such as Parkinson's disease (PD). Research suggests that lysosomes choke on the faulty brain proteins that accrue in inherited PD (see "Stuck in the Craw"). Whether autophagy helps protect against cancer--perhaps by culling broken-down mitochondria that can trigger DNA damage or by killing abnormal cells--is controversial. Some researchers even suggest that autophagy promotes uncontrolled growth by helping cells survive inside a tumor, where nutrients are scarce. The question remains unresolved because "nobody has found any direct links" between autophagy and cancer, says cancer biologist Jason Weber of Washington University School of Medicine in St. Louis, Missouri.

Reef and colleagues have now identified such a link while studying the tumor-fighting protein ARF. In response to molecules that stimulate cell division, ARF activates p53, which curbs tumor growth by stopping damaged cells from dividing or spurring them to commit suicide. Mice lacking ARF and p53 sprout more tumors than mice missing only p53, suggesting that ARF also fights cancer independent of p53. The researchers discovered that mouse cells manufacture a short variant of ARF in addition to the full-length form. The long version of ARF labors in the nucleus, and the stumpy version slips into the mitochondria, the cell's power plants. When the researchers engineered cells to pump out extra quantities of the short form, mitochondria lost their electrical charge, sapping their ability to produce energy. Cranking up quantities of the truncated ARF also prodded large numbers of cells to perish. Autophagy kicked into overdrive in moribund cells. Numerous autophagosomes sprang up, and the researchers observed them gobbling mitochondria and other cellular components. To confirm that rampant autophagy triggered the die-off, the researchers used small RNA molecules to block two proteins necessary for autophagy. The death rate plummeted. Moreover, doomed cells didn't activate a protein called caspase-3 that helps incite apoptosis, another suicide mechanism. That finding suggests that apoptosis isn't the cause of the cells' demise. Overall, the researchers conclude, the abbreviated ARF shorts out mitochondria and drives cancer cells to eat themselves to death. How the presumptive mitochondrial power loss connects to their self-sacrifice isn't clear.

The result is surprising because researchers often see shortened versions of proteins but dismiss them as junk, says molecular oncologist Steven Grossman of the University of Massachusetts Medical School in Worcester. Cancer biologist Charles Sherr of St. Jude Children's Research Hospital in Memphis, Tennessee, cautions that the team's measurements suggest that the truncated protein breaks down quickly. He questions whether it can last long enough to have an effect in cells that produce normal rather than surplus quantities of the protein. Identifying the truncated protein provides a tool to help researchers probe self-eating's role in cancer prevention, says Weber. Future work might reveal how we can prod cancer cells to develop a taste for themselves.

May 24, 2006
  1. S. Reef et al., A short mitochondrial form of p19ARF induces autophagy and caspase-independent cell death. Mol. Cell 22, 463-475 (2006). doi:10.1016/j.molcel.2006.04.014 [CrossRef][Medline]
Citation: M. Leslie, Shortcut to Death. Sci. Aging Knowl. Environ. 2006 (9), nf15 (2006).

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