Dartmouth Researchers Target Rapid Destruction of a Protein Responsible for Cancer Cell Resistance to Therapy

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Citations NIH RO1 CA057359; Journal of Biological Chemistry

Newswise — (Lebanon, NH, 8/11/14) —Dartmouth cancer researchers at Norris Cotton Cancer Center found a means of causing the elimination of a protein that maintains cancer cell viability; the results of the study appear in the August 8 issue of The Journal of Biological Chemistry.

“These findings may lead to a new target for chemoresistant cancer cells,” said Ruth W. Craig, PhD, professor of Pharmacology & Toxicology, Geisel School of Medicine at Dartmouth, Hanover, NH, who is primary author of the peer reviewed article. “These cells are resistant to multiple types of standard chemotherapeutic agents because of over-expression of Myeloid Cell Leukemia-1 (Mcl-1), however, Mcl-1 expression plummets when we inhibit one particular enzyme and then cancer cells subsequently die.”

The Mcl-1 protein is frequently over-expressed in cancer; it is present not only in leukemia and lymphoma but also in a host of solid tumors. While Mcl-1 is expressed in a highly-controlled fashion in normal cells, its over-expression and lack of destruction maintains the viability of cancer cells and renders them resistant to chemotherapy. When high levels of this protein are maintained, the patient’s cancer cells survive multiple types of drug treatment.

The research found that an enzyme that removes phosphate groups from Mcl-1 is critical in terms of maintaining its expression in cancer. This enzyme, known as protein phosphatase 2A (PP2A), can be inhibited to stop the removal of phosphate groups from a regulatory motif in Mcl-1 referred to as the PEST region (enriched with amino acids Proline, glutamic acid, Serine, and Threonine). Inhibition of the removal of phosphate groups, such as at Threonine-163 and Serine-159, targets the Mcl-1 protein for rapid destruction and, shortly thereafter, the cancer cells die.

“PP2A is a complex multi-subunit enzyme and we hope to identify more specifically which form of PP2A is involved in dephosphorylating Mcl-1,” said Craig. “This could give a more specific way of causing Mcl-1 destruction.”

The study was funded in part by NIH grant # RO1CA057359.

[Figure Caption: In lymphoma cells that overexpress the viability-promoting Mcl-1 protein, shown at the lower left, inhibition of protein phosphatase PP2A acts at a turning point to destroy Mcl-1 and stop its effects. A motif in Mcl-1 is phosphorylated (yellow rectangle with green P) to stabilize the protein in cancer. Inhibition of PP2A maintains phosphorylation at an adjacent site (red P), irreversibly targeting Mcl-1 for degradation and promoting cell death, as shown at the lower right.]

About Norris Cotton Cancer Center at Dartmouth-Hitchcock
Norris Cotton Cancer Center combines advanced cancer research at Dartmouth and the Geisel School of Medicine with patient-centered cancer care provided at Dartmouth-Hitchcock Medical Center, at Dartmouth-Hitchcock regional locations in Manchester, Nashua, and Keene, NH, and St. Johnsbury, VT, and at 12 partner hospitals throughout New Hampshire and Vermont. It is one of 41 centers nationwide to earn the National Cancer Institute’s “Comprehensive Cancer Center” designation. Learn more about Norris Cotton Cancer Center research, programs, and clinical trials online at cancer.dartmouth.edu.

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