Cholesterol or other sterols are critical for sonic hedgehog signaling, medullablastoma
By Melissa Lee Phillips | May 16, 2006
Inhibitors of cholesterol synthesis -- such as statin drugs -- may inhibit growth of some tumors, according to a paper in this week's Proceedings of the National Academy of Sciences. The authors found that sterols or their derivatives have a critical effect on the sonic hedgehog (Shh) signaling pathway in medulloblastoma cells, suggesting that blocking sterols could stop medulloblastoma and other Shh-dependent tumors.
"The implication for treatment of human cancer is actually pretty good," said David Robbins of Dartmouth Medical School in Hanover, NH, who was not involved in the study. "Medulloblastoma cells seem to be very susceptible to changes in cholesterol biosynthesis."
Shh signaling, when unregulated, promotes the formation of some human tumors, especially medulloblastoma and basal cell carcinoma. A loss-of-function mutation in the tumor-suppressor gene PATCHED is the most common mutation underlying uncontrolled Shh signaling. The Patched protein normally inhibits downstream Shh target genes by blocking function of the protein Smoothened.
Scientists have shown that the Shh signaling pathway depends on sterol synthesis, said senior author Matthew Scott of Stanford University in Palo Alto, Calif., but it wasn't known which member of the sterol synthetic pathway was the key ingredient. As part of the sterol synthetic pathway, acetyl CoA is converted to isoprenoids, then to sterols, and finally to steroids.
Scott and Ryan Corcoran, also of Stanford, treated mouse medulloblastoma cells with inhibitors that block various steps of the sterol synthetic pathway. They found that all inhibitors that block steps upstream of cholesterol synthesis, including a statin, reduced medulloblastoma cell proliferation. An inhibitor that blocked the conversion of sterols to steroids, however, had no effect on cell proliferation, suggesting that cholesterol or a derivative is likely the crucial product in medulloblastoma cell proliferation, Scott said.
They found that the inhibitor that reduced medulloblastoma cell proliferation also reduced expression of Patched and of the Shh target gene gli1 -- to an extent similar to that of the known Shh pathway inhibitor cyclopamine.
The inhibition of both Shh signaling and medulloblastoma cell proliferation was reversed when the researchers added back cholesterol or one of several oxysterol derivatives of cholesterol. Some oxysterols encouraged proliferation more strongly than unmodified cholesterol, but it's impossible to know which molecule is regulating this pathway in vivo, Scott said. Corcoran and Scott also showed that the proliferative effects of an oxysterol can be blocked by a known Smoothened inhibitor, which they say suggests that sterols normally activate Smoothened.
"The paper has really widespread implications for a large field," said Anna Marie Kenney of Memorial Sloan-Kettering Cancer Center in New York, who was not involved in the study. "All of the hedgehog family members signal through a very highly conserved mechanism," she said, "so other cancers where the hedgehog pathway is involved may also be sensitive to sterols."
Cynthia Wetmore of the Mayo Clinic College of Medicine in Rochester, MN, who was not involved in the research, agreed that "their data are convincing," but the results "may not be entirely predictive of how human tumor cells would react." All of the experiments were performed on mouse tumor cells with p53 mutations, and it's possible that this mutation -- which is not usually seen in human tumors -- could affect their results, Wetmore told The Scientist.
Also, since medulloblastoma usually affects children, it's important to investigate whether cholesterol synthesis inhibitors influence normal brain development, Wetmore added. "Cholesterol and lipid metabolism is very important to the developing brain," she said, and "it remains to be seen if the statins are specific for tumor cells."
If the results from cell culture hold up in living tissue, Scott said, it may be possible to develop a treatment that combines cholesterol synthesis inhibitors -- such as the statins used to lower cholesterol levels in people at risk of cardiovascular disease -- with Smoothened antagonists, which are already in clinical trials as cancer treatments.
"There are lots of hedgehog-dependent tumor cells that are affected by these Smoothened antagonists," Robbins told The Scientist. "The idea of combining a cholesterol biosynthetic inhibitor with a Smoothened antagonist is an attractive one."
Melissa Lee Phillips
Links within this article
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R.B. Corcoran, M.P. Scott, "Oxysterols stimulate sonic hedgehog signal transduction and proliferation of medulloblastoma cells," PNAS, published online May 15, 2006.
J. Weitzman, "Stopping hedgehogs," The Scientist, August 30, 2002.
C. Wetmore, "Sonic hedgehog in normal and neoplastic proliferation: insight gained from human tumors and animal models," Current Opinion in Genetics and Development, February 2003.
C. Raffel et al., "Sporadic medulloblastomas contain PTCH mutations," Cancer Research, March 1, 1997.
D. Kalderon et al., "Transducing the hedgehog signal," Cell, October 27, 2000.
M.K. Cooper et al., "Teratogen-mediated inhibition of target tissue response to Shh signaling," Science, June 5, 1998.
Anna Marie Kenney
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J.A. Williams et al., "Identification of a small molecule inhibitor of the hedgehog signaling pathway: effects on basal cell carcinoma-like lesions," PNAS, April 15, 2003.
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