Plant gene related to cancer treatment may foster new oncology drugs

11/22/05



Molecules in laboratory plants grown in the Purdue University horticulture greenhouses are helping cell biologist Angus Murphy unravel why human cells reject cancer drugs. (Purdue Agricultural Communication photo/Tom Campbell)
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WEST LAFAYETTE, Ind. - Two proteins involved in the process that controls plant growth may help explain why human cells reject chemotherapy drugs, according to an international team of scientists.

Researchers from Purdue University and Kyoto University in Japan have shown for the first time that proteins similar to multi-drug resistant proteins in humans move a plant growth hormone into cells, said Purdue plant cell biologist Angus Murphy. Because plant proteins called P-glycoproteins (PGPs) are closely related to human P-glycoproteins that impact chemotherapy effectiveness, discovery of methods to control the plant protein's activity may aid in development of therapies to reduce drug dosages administered to cancer patients, Murphy said.

Murphy is corresponding author of the study published in the November issue of Plant Cell. He also is corresponding author of a related article published in October's Plant Journal.

"Results of this research will give us a better idea of the functioning of the multi-drug resistance process in which human cancer cells reject anticancer treatments," Murphy said.

Results of the two studies suggest a previously unknown relationship between two protein families involved in this process, he said. Working together, the proteins apparently move molecules of the plant growth hormone auxin through cell walls. In humans, related proteins rid cells of toxins such as cancer drugs.

"The findings of these two studies have important implications for biomedicine because we now can identify the parts of these proteins that determine whether cells take up or throw off different molecules, such as cancer drugs," Murphy said.

In the Plant Journal study, Murphy and his collaborators at the University of Zurich showed for first time that PGP1, a P-glycoprotein from the commonly used experimental plant Arabidopsis, directly transports auxin out of plant cells and also out of yeast and mammalian cells. In the Plant Cell study, they found that other PGP proteins move auxin into cells.

"Auxin molecules essentially are pulled through the cell membrane by PGP transport proteins," Murphy said. "It's an energetic process that happens like pulling a rope through something sticky."

Both the multi-drug resistant PGPs in people and plants are part of a large family of proteins, called ATP-binding cassette (ABC) proteins, that act as delivery trucks to detoxify cells, send messages from cell to cell to influence biochemical reactions, and to regulate those reactions. The ABC proteins are so named because they must bind with ATP, the main cell energy source, in order to fulfill their mission.

The best known member of another class of transport proteins, PIN1, also may be a transporter, but appears to function primarily as an aide rather than the delivery truck for auxin transport, Murphy said. This finding revealed that PINs and PGPs may function together in long-distance auxin transport, according to the Plant Journal article. Named for the pin-shaped appearance of the mutant originally used to identify the gene that directs the activities of PIN1, these proteins are members of the major protein family, called facilators, that aid processes such as hormone transport.

Recent evidence suggests that teamwork between PGP and PIN proteins determines the direction auxin moves and, therefore, how the plant develops, Murphy said. In plants, shape, height and bending in response to light and gravity are largely determined by the direction and amount of auxin moving through their tissues.

Murphy and his collaborators on the Plant Journal study found that PGP1 and PGP19 move the hormone out of cells.

In the November Plant Cell report, Murphy's research team reported that another P-glycoprotein, PGP4, functions in the opposite direction, providing the boost needed to import the hormone auxin into cells and to increase the amount transported.

"With these two studies, we've shown for the first time that both the uptake and release of molecules are mediated by interaction between the PGP transporter proteins and PIN facilitator proteins," Murphy said.

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