Protein Identified that Prevents Apoptosis in Normal Cells

A recent study describes a mechanism involving the Bcl-xL protein that explains why chemotherapeutic drugs that damage cancer cell DNA and cause the death of the cells do not damage normal, healthy cells. The study was published in the October 4, 2002, issue of Cell.

"The standard answer is that tumor cells are dividing and normal cells are not,” stated senior author Dr. Steve J. Weintraub, assistant professor of surgery at Washington University School of Medicine (St. Louis, MO, USA). "But that is an observation, not an explanation.”

The investigators exposed cancer cells from bone, ovarian, and other tumors to the anti-cancer drug cisplatin. Examination of the Bcl-2 proteins from the cells that had died by apoptosis revealed that in each case one member of the Bcl-2 family, the protein Bcl-xL, had been modified by deamidation, a reaction that modified two amino acids in Bcl-xL. Deamidiation of Bcl-xL changed the shape of the protein molecule and rendered it inactive. In its active state, Bcl-xL was tightly bound to another Bcl-2 protein that when free triggered apoptosis. When Bcl-xL was inactivated by deamidation, it released the second protein, and apoptosis could proceed.

In a follow-up study, the researchers treated a line of healthy, nondividing human fibroblasts and several lines of mouse fibroblasts with cisplatin. In some of the cells, the investigators had artificially inactivated the Bcl-xL protein. They found that cells with normal Bcl-xL were not affected by the drug, while those with inactive Bcl-xL died by apoptosis, indicating they were now susceptible to cisplatin.

"Our findings show that if Bcl-xL is inactivated through a chemical process known as deamidation, DNA-damaging chemotherapy will kill even healthy cells,” explained Dr. Weintraub. "Normal cells somehow suppress the signal that throws the switch and avoid self-destructing. Tumor cells that suppress the same signal also might be resistant to chemotherapy drugs.”



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