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Researchers target rapid destruction of protein responsible for cancer cell resistance to therapy

Date:
August 14, 2014
Source:
Norris Cotton Cancer CenterDartmouth-Hitchcock Medical Center
Summary:
Researchers have identified an enzyme that may help break down chemoresistance in cancer cell that overexpress Myeloid Cell Leukema-1 (Mcl-1). 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.

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.
Credit: Image courtesy of Norris Cotton Cancer CenterDartmouth-Hitchcock Medical Center

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."


Story Source:

The above story is based on materials provided by Norris Cotton Cancer CenterDartmouth-Hitchcock Medical Center. Note: Materials may be edited for content and length.


Journal Reference:

  1. S. K. Nifoussi, N. R. Ratcliffe, D. L. Ornstein, G. Kasof, S. Strack, R. W. Craig. Inhibition of Protein Phosphatase 2A (PP2A) Prevents Mcl-1 Protein Dephosphorylation at the Thr-163/Ser-159 Phosphodegron, Dramatically Reducing Expression in Mcl-1-amplified Lymphoma Cells. Journal of Biological Chemistry, 2014; 289 (32): 21950 DOI: 10.1074/jbc.M114.587873

Cite This Page:

Norris Cotton Cancer CenterDartmouth-Hitchcock Medical Center. "Researchers target rapid destruction of protein responsible for cancer cell resistance to therapy." ScienceDaily. ScienceDaily, 14 August 2014. <www.sciencedaily.com/releases/2014/08/140814123610.htm>.
Norris Cotton Cancer CenterDartmouth-Hitchcock Medical Center. (2014, August 14). Researchers target rapid destruction of protein responsible for cancer cell resistance to therapy. ScienceDaily. Retrieved September 23, 2014 from www.sciencedaily.com/releases/2014/08/140814123610.htm
Norris Cotton Cancer CenterDartmouth-Hitchcock Medical Center. "Researchers target rapid destruction of protein responsible for cancer cell resistance to therapy." ScienceDaily. www.sciencedaily.com/releases/2014/08/140814123610.htm (accessed September 23, 2014).

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