Malignant Cells Survive-and Replicate-Because Cancer-causing Molecule Jams Normal p53 Cell-suicide Trigger

Rockefeller Researchers Uncover Clue to Improving Cancer Chemotherapy

Colon tumors overproduce WISP-1 protein. Above: colorectal carcinoma cells positively stained with an antibody against WISP-1 (brown). The results, which were obtained in collaboration with Charles J. Di Como, Ph.D., and Carlos Cordon-Cardo, M.D., Ph.D., of the Memorial Sloan-Kettering Cancer Center, provide evidence that WISP-1 is a cancer-causing gene.

A cancer-causing molecule called WISP-1 may explain why some people with cancer do not benefit from chemotherapy while others with the same form of cancer respond to the treatment, according to researchers at The Rockefeller University. The findings, reported in the Jan. 1 issue of Genes and Development, suggest that drugs designed to block WISP-1 may increase the effectiveness of chemotherapy in colon cancer and perhaps other cancers.

“This research, for the first time, ties together several of the pathways that lead to cancer and shows how they are interlinked,” says senior author Arnold J. Levine, Ph.D., president of The Rockefeller University and head of its Laboratory of Cancer Biology.

Other authors include first author Fei Su, Ph.D., a postdoctoral fellow in Levine’s laboratory; Michael Overholtzer, a student in Levine’s laboratory; and Daniel Besser, Ph.D., a postdoctoral fellow in Rockefeller Professor James Darnell’s laboratory.

Chemotherapy kills cancerous cells by damaging their DNA. The cells essentially commit suicide when they sense that the damage is beyond repair. The molecule responsible for cell suicide is a protein that Levine named p53, which he co-discovered in 1979 while at Princeton University.

In research 10 years later, Levine found that p53 is a tumor suppressor, which prevents cancer – much as a “spell check” in a word processor catches and repairs mistakes. In the case of p53, the mistakes are mutations in a cell’s DNA genetic code. If the mistake cannot be repaired, p53 activates the cell’s suicide program. However, when p53 is blocked by WISP-1, as is shown to occur by Levine’s new research, mutations are not caught. Instead, cells with mutations survive and replicate unchecked, resulting in the uncontrolled cell growth that characterizes cancer.

Faulty p53 is responsible for some 55 percent of all human cancers, various studies have revealed.

Previous research by Levine and his colleagues showed WISP-1 promotes growth of cancer cells and is overproduced, or amplified, in colon cancer cells. In the Genes and Development paper, Levine and his Rockefeller colleagues found that WISP-1 thwarts the cell’s suicide mechanism by binding to the surface of cells damaged by chemotherapeutic drugs, thereby blocking p53-initiated cell death.

Michael Overholtzer, Fei Su and Daniel Besser have begun to elucidate the role of WISP-1 in cancer.

“Most proteins that contribute to cancer either promote cell growth or block cell death,” says Levine. “Now we know that WISP-1 does both, and the second activity – preventing cell death – is dependent on p53.”

WISP-1 works by activating Akt and Bcl-XL, two other proteins that interfere with the cell death program, and disabling a third molecule called cytochrome c. Akt and Bcl-XL operate in two separate pathways to promote a cell’s survival and block cell death, respectively. Under normal conditions, cytochrome c “leaks out” of mitochondria – the cell’s energy storage houses – and triggers cell death.

Su showed that WISP-1 inhibits the release of cytochrome c from mitochondria in response to DNA damage. The researchers propose that WISP-1 inhibits cytochrome c by increasing production of Bcl-XL, which blocks the release of cytochrome c even though p53 has been activated. This is the first time a link between p53 and Bcl-XL has been documented.

The researchers also found that WISP-1 works only in cells that contain p53, and it doesn’t work if the p53 gene is mutated. According to Levine, this finding helps explain the failure of chemotherapy in the 45 percent of cancers, like colon cancer, in which p53 is functioning properly and a positive response to chemotherapy would be expected.

“This may explain the poor correlation between response to chemotherapy and presence of p53, which we did not understand before now,” says Levine.

Levine and his colleagues also developed an antibody for WISP-1 and showed that the antibody can block WISP-1.

“We may be able to give an antibody against WISP-1 to cancer patients to enhance the effectiveness of chemotherapy,” says Levine.

WISP-1 is a member of the WNT pathway, which is involved in embryonic development and stimulates cell growth. Other researchers have shown that several proteins in the Wnt pathway play a role in cancer. Levine’s team has now linked for the first time two cellular pathways – WNT and p53 – that were previously thought to be unrelated. The WNT pathway begins cell division and prevents cell death, while p53 halts cell division and promotes cell death.

This research was supported in part by a grant from the federal government’s National Institutes of Health and a fellowship from the Susan G. Komen Breast Cancer Foundation. Levine, the Robert and Harriet Heilbrunn Professor of Cancer Biology, heads the Robert and Harriet Heilbrunn Laboratory of Cancer Biology at The Rockefeller University.

John D. Rockefeller founded Rockefeller University in 1901 as The Rockefeller Institute for Medical Research. Rockefeller scientists have made significant achievements, including the discovery that DNA is the carrier of genetic information. The university has ties to 21 Nobel laureates, six of whom are on campus. Rockefeller University scientists have received this award for two consecutive years: neurobiologist Paul Greengard, Ph.D., in 2000 and cell biologist Günter Blobel, M.D., Ph.D., in 1999, both in Physiology or Medicine. At present, 33 faculty are elected members of the U.S. National Academy of Sciences. Celebrating its Centennial anniversary in 2001, Rockefeller-the nation’s first biomedical research center-continues to lead the field in both scientific inquiry and the development of tomorrow’s scientists.