UC San Diego Health Sciences News

Posted: May 5, 2015 at 2:15 pm

Centrosomes and Cancer: Settling an Old Debate

Early last century, German biologist Theodor Boveri observed that cancer cells often harbor multiple copies of a cellular structure known as the centrosome. He was also the first to suggest that the extra centrosomes drive cancer. Researchers have since learned a great deal about the structure and many functions of Boveris special organ of cell division. But why cancer cells harbor multiple copies of this organelle and whether they are addicted to having so many has remained unanswered. So has the question of whether healthy human cells even require centrosomes to divide, making more cells. Now, 101 years after Boveri first aired his suspicions, researchers may have some answers.

A new study, published April 30 in Science, shows that while cancer cells are not addicted to multiple centrosomes, healthy cells absolutely require them to proceed with cell division. In the absence of centrosomes, healthy cells dont divide, while malignant cells continue dividing and multiplying.

Our results have settled a long-running debate in cell biology, said co-senior author Karen Oegema, PhD, professor of cellular and molecular medicine at University of California, San Diego School of Medicine and member of the Ludwig Institute for Cancer Research. Centrosomes make things so much better for healthy dividing cells, that cells have a protective mechanism that halts their division if they lose centrosomes.

Ordinarily, the resting cells single centrosome serves as an organizing center for the cells skeleton. When a cell divides, however, the centrosome takes on another function. The centrosome duplicates and helps ensure chromosomes are distributed equally between the two daughter cells. Many cancer cells contain multiple centrosomes, and this error contributes to the misdistribution and abnormal numbers of chromosomes in daughter cells.

Still, it wasnt clear that centrosomes are absolutely needed for cell division. Biologists have long known that other mechanisms exist to separate chromosomes. The growing feeling among a number of cell biologists is that the centrosome is like the appendix of the cell, said co-senior author Andrew Shiau, PhD, director of the Ludwig Institutes Small Molecule Discovery Program in San Diego and visiting scientist at UC San Diego.

Earlier studies had sought to resolve the issue by cutting centrosomes out of cells or destroying them with lasers. But both normal and cancer cells treated this way simply remade their lost centrosomes, and then continued dividing.

To get around this limitation, in this study the researchers designed and synthesized a molecule that specifically and reversibly inhibits an enzyme named Plk4, which controls the assembly of centrioles barrel-like protein structures from which centrosomes are made. They then showed that exposure to this inhibitor, called centrinone, eliminates centrosomes from both healthy cells and cancerous ones. When the compound was removed, cancer cells reverted to precisely the number of centrosomes they had before exposure to the molecule.

This was in marked contrast to what normal cells would do when we persistently removed centrosomes, Oegema said. Normal cells arrested their growth when their centrosomes were absent. This suggests that they absolutely require centrosomes for division, which was not at all the thinking in the field.

The researchers show that the pause in the division of healthy cells is governed by a protein named p53, which is mutated in about half of all cancers. Levels of p53 were elevated in cells treated with centrinone. When the protein was temporarily inactivated in normal cells, they too failed to arrest upon exposure to centrinone.

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UC San Diego Health Sciences News

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