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Sentinel Against Ovarian Cancer
Basic research on the organic molecule LPA by JANE M. SANDERS | |
ONE MEMBER OF a family of fat-like molecules called lysophospholipids strongly promotes ovarian and uterine cancer tumor cell growth and metastasis. This compound – called lysophophatidic acid, or LPA – is being studied by researchers at Georgia Tech.
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Its role is important to scientists searching for an early detection marker and new drugs to treat the often-lethal ovarian cancer, which has few or no symptoms in its early stage.
The Georgia Cancer Coalition is funding Harish Radhakrishna, an assistant professor of biology who began a one-year pilot study on LPA last year, to gather more data on his recent findings.
Radhakrishna’s investigation was prompted by a 1999 Cleveland Clinic study comparing LPA levels in the blood and body cavity fluid of ovarian cancer patients at varying stages of the disease. Researchers found that, at all stages of the cancer, patients had elevated levels of LPA compared to healthy individuals. They further discovered that LPA stimulates growth and metastasis of various tumor cell types, including lung, breast, prostate and ovarian.
“Although LPA has a normal physiological function, such as stimulating the contraction of muscles and participating in normal cell growth, cancer cells often subvert that good role,” Radhakrishna explains.
His team’s investigation narrowed when Radhakrishna and his Ph.D. student Mandi Murph found that application of LPA to breast and lung cancer cells greatly diminished the activity of a critical “sentinel” protein, p53, which is mutated in half of all human cancers.
“This is important because all cells have several ‘guard posts’ set up to ensure that only normal cells can divide,” Radhakrishna explains. “The p53 protein is one of the most important ‘sentinels’ in normal cells; it makes sure the cell does not divide if its DNA is damaged.”
If the DNA in a cell is damaged, p53 stops the cell from dividing and triggers a pathway to fix the damage and then lets the cell continue to divide. But if the DNA is damaged beyond repair, p53 triggers the destruction of the cell through a process called programmed cell death or apoptosis.
“If you’re a cancer cell, your goal is to bypass these normal ‘checkpoints’ so that you can divide uncontrollably. One of the best ways to do this is to mutate and inactivate p53. Our finding that LPA decreases p53 function suggests that perhaps this is one of the ways that LPA enhances cancer cell proliferation,” Radhakrishna adds.
For the pharmaceutical industry, this process could be a target for development of an anti-cancer drug, Radhakrishna says. So he and Murph are studying how the LPA signal gets from the receptor at the cell surface to the point of inactivating p53. They have found that LPA enhances the destruction of p53 and are now focusing on the steps it takes to accomplish that task in breast, lung and ovarian cancer cells.
Preliminary findings from Radhakrishna’s pilot study are reinforcing his and other researchers’ earlier published findings that LPA promotes cancer cell growth by inactivating p53. He hopes this data will garner his team a long-term grant to determine the specific pathway that LPA uses to achieve this effect.
In related cancer research, Radhakrishna and his team recently found that currently used drug analogues of naturally occurring compounds called cyclic AMP prevent LPA-stimulated growth of ovarian cancer cells. They do so by preventing the activation of an important transcription factor that up-regulates the expression of genes that promote cell growth. Knowing this pathway opens the door to additional drug targets that might be used in combination with the drug analogues of cyclic AMP to boost their effectiveness, Radhakrishna explains. Their work was recently published in the journal Cellular Signaling.
In another early-stage project, Radhakrishna and University of Georgia Professor of Genetics John McDonald – who will become chairman of the Georgia Tech School of Biology in July 2004 – are collaborating to determine how the expression pattern of LPA receptors varies between ovarian cancer cells and normal ovarian cells. Previous research showed that the types of receptors expressed by cells changes as cells become cancerous.
In ovarian cancer cells, Type 1 receptors are sometimes shut off, while Types 2 and 3 are expressed. Researchers believe the latter two types are responsible for stimulating the growth of ovarian cancer cells. McDonald and Radhakrishna are investigating why cancer cells express Type 2 and 3 receptors instead of others.
“Everything we do in my lab deals with LPA, which has a lot of effects on normal and cancerous cells,” Radhakrishna notes. “The common theme is that the receptor proteins to which LPA binds are the real mediators of all of these various effects.
“Our goal is to find out how cells control their activity so that someday pharmaceutical compounds can be developed that could either increase or decrease their activity. This information is extremely important for its broad applications to normal and pathological processes.”
For more information, contact Harish Radhakrishna at 404-385-1323 or
harish.radhakrishna@biology.gatech.edu.
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Last updated: July 7, 2004