Printer Friendly

Cancer roadblock on cholesterol pathway.

Cancer roadblock on cholesterol pathway

The road to cholesterol synthesis is paved with more than a dozen chemical precursors. Biochemists now report that blocking the production of one of these precursors yields an unexpected payoff: A protein involved in pancreatic and colon cancers can no longer prompt cellular changes associated with cancerous growth.

The finding, they say, establishes the first major link between cholesterol synthesis and cancer. It also suggests a new arsenal of anticancer drugs -- possibly including a compound now marketed as a cholesterol-lowering agent -- that target specific cholesterol precursors. On a more basic level, the discovery may help clarify the chemical changes and genetic mutations that trigger some genes, called oncogenes, to cause cancerous alternations in cells.

Researchers at the University of California, Berkeley, and the Lawrence Berkeley Laboratory inhibited the formation of mevalonate, a precursor to cholesterol and other compounds. Without melalonate, the protein encoded by the ras oncogene cannot attach to cell membranes -- a critical step in promoting pancreatic and colon cancers. Though the protein retains its ability to promote cancer, without membrane attachment it never gets the chance.

In unfertilized frog eggs, the group observed that human oncogenic ras -- a rare, mutant relative of the normal ras protein found in cells -- caused breakdown of the envelope surrounding the cell nucleus, indicating the protein induced cell division. But preinjecting the eggs with compactin or lovastatin -- drugs that block the formation of mevalonate -- prevented oncogenic ras from maturing and initiating envelope breakdown. Adding mevalonate to these eggs restored the ras protein's ability to cause envelope breakdown, the researchers report in the July 28 SCIENCE.

Because physicians already prescribe lovastatin to lower cholesterol in some patients (SN: 9/12/87, p.166), researchers are eager to know if the drug also lowers the incidence of cancers associated with the ras oncogene. But the California scientists and others emphasize that the anticancer potential of any such drug would hinge not on its cholesterol-lowering properties per se but on its ability to block precursors that assist oncogenic ras. In fact, note study coauthors Jasper Rine and William R. Schaefer, better anticancer drugs might come from compounds that act on another cholesterol precursor, farnesyl pyrophosphate, which derives from mevalonate and serves to "glue" ras to cell membranes.

"Proteins such as ras are water-loving molecules that have trouble attaching to the greasy cell membrane," Rine explains. "The protein requires a little dab of grease to attach." Upon detecting functional similarities between a yeast sex hormone and the yeast form of ras, the researchers, hypothesized that farnesyl provides the missing dab of grease at the tail end of the ras protein.

Research reported by British investigators in the June 30 CELL confirms the location of farnesyl's attachment to ras. And a study by scientists at the La Jolla (Calif.) Cancer Research Foundation, to appear in an upcoming PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES, chemically identifies farnesyl as the grease dab. Rine told SCIENCE NEWS his group plans to search for the enzyme that enables farnesyl to attach to ras. Once the enzyme is identified, he says, researchers might be able to developed drugs that inhibit it.

A more basic challenge, comments Nobel laureate Michael S. Brown, a cholesterol researcher at the university of Texas Southwestern Medical Center in Dallas, is to determine whether the link between cholesterol synthesis and the ras oncogene is "a mere evolutionary fact without deeper significance" or nature's way of activating oncogenes.
COPYRIGHT 1989 Science Service, Inc.
No portion of this article can be reproduced without the express written permission from the copyright holder.
Copyright 1989, Gale Group. All rights reserved. Gale Group is a Thomson Corporation Company.

Article Details
Printer friendly Cite/link Email Feedback
Author:Cowen, R.
Publication:Science News
Date:Jul 29, 1989
Words:574
Previous Article:Land plants' algal roots.
Next Article:Clues to an ancient upside-down ocean.
Topics:


Related Articles
Oxidized lipids: a key to heart disease?
High cholesterol = high cancer risk?
A tangle of fibers: scientists examine how different dietary fibers produce their health benefits.
Cholesterol-cancer clues.
Is cholesterol lowering with statins the gold standard for treating patients with cardiovascular risk and disease? (Editorial).
Fatty findings: Genes that regulate fat may affect a variety of diseases.
NIH roadmap for medical research.
Breast cancer & HDL.
Anti-inflammatory, anticholesterol drugs vs. cancer.

Terms of use | Copyright © 2016 Farlex, Inc. | Feedback | For webmasters