Gene found to contribute to 50% of resistance, according to study in Molecular Cancer Research.

NCI researchers have discovered that increased expression of the SIRT1 gene plays a role in cancer patients developing resistance to cisplatin. They suggest that SIRT1 alters the function of mitochondria in cells and reduces the uptake and use of glucose within them.

In this study, investigators first generated cells that were resistant to the drug by exposing them to cisplatin in the laboratory. They found that expression of the SIRT1 gene increased three to fivefold as the levels of cisplatin were increased, producing increasing levels of resistance in the cells. On the other hand, the researchers found that cisplatin-resistant cancer cells became more sensitive to the drug when the level of SIRT1 expression was reduced. By decreasing the levels of SIRT1 expression three to fivefold, the cancer cells became approximately twofold more sensitive to cisplatin.

“It appears that SIRT1 contributes to 50 percent of the cellular resistance to cisplatin, but it does not account for all of the resistance,” says Michael Gottesman, M.D., of NCI’s Center for Cancer Research.

The researchers specifically found that cancer cells increased their expression of SIRT1 and became more resistant to cisplatin treatment as the level of glucose in their environment was reduced. They observed that the uptake of glucose in resistant cells was four to fivefold less than in cells that were sensitive to cisplatin. Oxygen consumption, an indicator of glucose use and energy production, decreased by 30%  to 60% compared to cisplatin-sensitive cells.

The team also noticed that as cellular resistance to cisplatin increased, the potential of mitochondria to produce energy decreased. This indicated that the metabolic role of mitochondria in resistant cells is different from that in cells that are sensitive to the drug. The researchers found that mitochondria of resistant cells were smaller, and the internal structures were irregular compared to the mitochondria of cells that were sensitive to the drug.

In addition to NCI, researchers from the National Heart, Lung, and Blood Institute, which is part of the NIH, the FDA, and the National Center of Nanoscience and Technology, Beijing, participated in the study.

The results appears in the September 15 issue of Molecular Cancer Research.


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