Cancer: New Sensor Tracks Zinc in Cells

Photo: Zinc

Zinc is found in every tissues of the body. Most of it is bound, but a small part is mobile and thought to be critical in proper functions of organs;
© Zanier

Shifts in zinc's location could be exploited for early diagnosis of prostate cancer. A new optical sensor created at MIT tracks zinc within cells and should help researchers learn more about its functions.

As an essential nutrient, zinc is found in every tissue in the body. The vast majority of the metal ion is tightly bound to proteins, helping them to perform biological reactions. Tiny amounts of zinc, however, are only loosely bound, or "mobile," and thought to be critical for proper function in organs such as the brain, pancreas, and prostate gland. Yet the exact roles the ion plays in biological systems are unknown.

The sensor, which can be targeted to a specific organelle within the cell, fluoresces when it binds to zinc, allowing scientists to determine where the metal is concentrated. The MIT chemists who designed the sensor have already used it to shed light on why zinc levels, normally high in the prostate, drop dramatically in cancerous prostate cells.

"We can use these tools to study zinc trafficking within prostate cells, both healthy and diseased. By doing so we are trying to gain insight into how zinc levels within the cell change during the progression of prostate cancer," says Robert Radford, an MIT postdoc who led the project. Radford works in the lab of Stephen Lippard, the Arthur Amos Noyes Professor of Chemistry. Researchers in Lippard's lab are now working on exploiting similar fluorescent sensors to develop a diagnostic test for early detection of prostate cancer, which is the second leading cause of cancer death in American men, but is considered very treatable if caught early enough.

Among its known roles, zinc helps to stabilize protein structure and catalyzes some cellular reactions. In the prostate, zinc is believed to help with reproductive functions by aiding in the accumulation of citrate, a component of semen. Within mitochondria of epithelial prostate cells, zinc has been shown to inhibit the metabolic enzyme aconitase. By blocking the activity of aconitase, zinc truncates the citric acid cycle, the series of reactions that produce ATP, the cells' major energy currency.

Scientists have theorized that when prostate cells become cancerous, they banish zinc from mitochondria (the cell structures where most ATP production occurs). This allows the cancer cell to produce the extra energy it needs to grow and divide. "If a cell is dividing uncontrollably and it needs a lot of chemical energy, then it definitely would not want zinc interfering with aconitase and preventing production of more ATP," Radford says. The new MIT study supports this theory by showing that, although cancerous prostate cells can absorb zinc, the metal does not accumulate in the mitochondria, as it does in normal prostate cells.

This finding suggests that, in normal cells, zinc is probably transported into mitochondria by a specialized transport protein, but such a protein has not been identified, Radford says. In cancer cells, this protein might be inactivated.

"The identification of intracellular targets for mobile zinc is an important step in understanding its true function in biological signaling. The next steps will involve discovery of the specific biochemical pathways that are affected by zinc binding to receptors in the organelles, such as proteins, and elucidating the structural and attendant functional changes that occur in the process," Lippard says.; Source: Massachusetts Institute of Technology