Tuesday, April 28, 1998
Vaults may hold help for tumor drug resistance
RESEARCH: Biochemists link cellular structures with aid in
chemotherapy research
By Matt Grace
Daily Bruin Contributor
Nearly a decade after discovering new cellular structures, known
as a vaults, scientists have yet to find out what they do. However,
their role in tumor drug resistance offers a clue.
The vaults are found in nearly every type of living organism –
from human beings to slime molds – and the genes for the vaults
vary little among different species.
By cellular standards, vaults are large, nearly three times the
size of the ribosomes – the protein factories of the cell – and are
relatively abundant. The mysterious particle, shaped like a beer
barrel, has been linked by UCLA biochemists Valerie Kickhoefer and
Leonard Rome to a phenomenon in cancer research known as multidrug
resistance.
The ability of cancer cells to develop resistance to
chemotherapy directly correlates with the number of vaults present
in the cells.
This could potentially eliminate one of the fundamental problems
in cancer treatment and at the same time provide keen insight into
the vault’s behavior.
"I think we’re closer now than we’ve ever been," said Leonard
Rome, senior associate dean for research at the UCLA School of
Medicine.
Although the major objective of Rome’s laboratory is to find out
what vaults do, the connection between vault number and drug
resistance represents a significant leap forward.
Drugs could either piggyback inside of a vault and make them
less toxic, or vaults could prevent chemotherapeutic drugs from
interfering with the nucleus.
One of the strongest lines of evidence showing that vaults are
molecular transporters comes from research by Dutch cancer
researcher and immunologist Rik Scheper involving tumor cells that
undergo multidrug resistance
"In many cases a tumor will be sensitive to chemotherapy at
first, but then after a short period of time it will develop
resistance to the drug," Rome said.
In his research, Scheper confirmed that a high concentration of
major vault protein in normal cell is the best predictor that cell
will become drug-resistant.
This discovery provided drug manufacturers with a framework to
increase sensitivity to cancer cells with multidrug resistance
which could lead to new cancer treatments.
"The multi-drug resistance connection is interesting, but it
hasn’t yet told us what vaults do," Rome said. "The major object of
the lab is figure out what they do."
"Until we figure out what they do, the multidrug resistance
connection will still be somewhat cloudy."
"From their shape and from their size we speculate that they
might be carrying something in the cell," Rome said.
"Under certain conditions the particle can come apart, and both
sides can open," Rome said. "And when it does, it opens into these
flowers."
The "flowers" consist of eight protein petals attached to a
ring. When the flowers come together they form a hollow structure
capable of carrying molecular cargo.
Rome’s laboratory began a collaboration with structure biologist
Phoebe Stewart to obtain detailed maps of the vault structure and
possibly gain new insight into its function.
"If you understand the structure, it helps you to understand the
function," said Stewart, an assistant professor in department of
molecular and medical pharmacology.
"Our goal is to understand the molecular architecture, and
together with (Rome’s) experiments this should help us to
understand the function of the vault and also how it does what it’s
designed to do," Stewart said.
"The next step is to show that vaults are directly involved by
either increasing the number of vaults in the cell by showing that
it becomes more resistant, or decreasing the number of vaults in
the cell showing that it becomes more sensitive," Rome said.
Scientists are currently looking for ways to deplete the vault
count in tumor cells that are multidrug resistant, making them
chemosensitive, according to Valerie Kickhoefer, senior research
associate and biochemist at UCLA.
"Other people in the lab are trying to figure out the function
of vaults in normal cells," Kickhoefer said.
"If we can do those things – and I have every reason to be
optimistic that we can – we will have destroyed one of the most
serious obstacles to successful cancer treatments."