How 'panic button' triggers cancer cells to elude toxic effects of drugs

London, Jan 30 (ANI): Under stressful conditions, yeast cells become unstable, and readily rearrange their chromosomes to facilitate rapid adaptation, according to a new study.

This "panic" response drives them to quickly evolve resistance to drugs, the New Scientist reported.

Researchers at the Stowers Institute for Medical Research demonstrated that stress itself could increase the pace of evolution by increasing the rate of chromosomal instability or aneuploidy.

The observation of stress-induced chromosome instability casts the molecular mechanisms driving cellular evolution into a new perspective and may help explain how cancer cells elude the body's natural defense mechanisms or the toxic effects of chemotherapy drugs.

"Cells employ intricate control mechanisms to maintain genomic stability and prevent abnormal chromosome numbers," said the study's leader, Stowers investigator Rong Li, Ph.D.

"We found that under stress cellular mechanisms ensuring chromosome transmission fidelity are relaxed to allow the emergence of progeny cells with diverse aneuploid chromosome numbers, producing a population with large genetic variation."

Aneuploidy is most often associated with cancer and developmental defects and has recently been shown to reduce cellular fitness.

To find out whether stress itself could increase the chromosome segregation error rate, graduate student and first author Guangbo Chen exposed yeast cells to different chemicals that induce various types of general stress and assessed the loss of an artificial chromosome.

This initial screen revealed that many stress conditions, including oxidative stress, increased the rate of chromosome loss ten to 20-fold, a rate typically observed when cells are treated with benomyl, a microtubule inhibitor that directly affects chromosome segregation.

The real surprise was radicicol, a drug that induces proteotoxic stress by inhibiting a chaperone protein, recalled Chen.

"Even at a concentration that barely slows down growth, radicicol induced extremely high levels of chromosome instability within a very short period of time," he said.

Continued growth of yeast cells in the presence of radicicol led to the emergence of drug-resistant colonies that had acquired an additional copy of chromosome XV.

Yeast cells pretreated briefly with radicicol to induce genomic instability also adapted more efficiently to the presence of other drugs including fluconazole, tunicamycin, or benomyl, when compared to euploid cells.

Interestingly, certain chromosome combinations dominated in colonies that were resistant to a specific drug. Fluconazole-resistant colonies typically gained an extra copy of chromosome VIII, tunicamycin-resistant colonies tended to lose chromosome XVI, while a majority of benomyl-resistant colonies got rid of chromosome XII.

Digging deeper, Chen grew tunicamycin-resistant yeast cells, which had adapted to the presence of the antibiotic by losing one copy of chromosome XVI, under drug-free conditions.

Before long, colonies of two distinct sizes emerged. He quickly discovered that the faster growing colonies had regained the missing chromosome. By returning to a normal chromosome XVI number, these newly arisen euploid cells had acquired a distinctive growth advantage over their aneuploid neighbors.

But most importantly, the fast growing yeast cells were no longer resistant to tunicamycin and thus clearly linking tunicamycin resistance to the loss of chromosome XVI.

The study has been recently published in the advance online issue of Nature. (ANI)