Scientists at La Trobe University published a study this week about a protein found in the flowers of ornamental tobacco plant that targets human cancer cells and destroys them. This raises the prospect of the deepest kind of irony: tobacco grown to produce drugs used to treat cancers caused by tobacco.
Mark Hulett, Marc Kvansakul and others from the Biochemistry Department used a range of techniques to examine the structure and function of a protein called NaD1. This protein is a type of defensin, a molecule that protects the plant from fungal infections. Why it also works on mammalian cancer cells is unknown, but is probably related to similarities of their cell membranes, where the action in this story takes place.
Of blebbing and lysis
In addition to testing the action of NaD1 against various fungi including yeast, the researchers tested its action on human cell lines known to come from lymphoma, cervical and prostate cancer. The action of interest was the disruption in cell membranes, which was measured in a variety of ways.
The leakage of ATP (a common molecule) was shown to happen within minutes of the introduction of NadD1 to lymphoma cells. Cervical cancers cells showed an increase in the uptake of a dye known as propidium iodide, demonstrating a breach of their cell membranes.
More dramatically, live confocal laser scanning microscopy was used to produce films showing cancer cells change shape in the presence of NaD1. Irregular shaped bulges in cells are known as blebs. Blebbing is like blowing up little balloons on the edges of cells, which often precede cell death. When membranes are broken, the contents of the cell are released in a process known as cell lysis.
NaD1 caused blebbing followed by lysis when introduced to human cancer cells. In other words, they developed bulges and then burst in the presence of this protein. There is unlikely to be a more satisfying experiment than one that results in the explosion of tumour cells.
Ligands in a cationic grip
Using a number of techniques including the X ray crystallography beam at the Synchrotron in Melbourne, they were able to describe the structure of the active component, which only worked when bound to lipids that came from the membrane of the target cell called PIP2. The final NaD1:PIP2 complex contained 14 copies of NAD1 bound to 14 copies of PIP2 in a unique ‘cationic grip’ configuration. The final complex was arch shaped with unusual fibrillar structures.
Written By: Susan Lawler
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