Protein Targeted For Cancer Drug Development Is Essential For Normal Heart Function

  Protein Targeted For Cancer Drug Development Is Essential For Normal Heart

PR Newswire

MEMPHIS, Tenn., July 10, 2013

St. Jude Children's Research Hospital discovers a role for a protein in
research that has implications for treatment of cancer and heart disease

MEMPHIS, Tenn., July 10, 2013 /PRNewswire-USNewswire/ -- St. Jude Children's
Research Hospital scientists have discovered that a protein used by cancer
cells to evade death also plays a vital role in heart health. This dual role
complicates efforts to develop cancer drugs that target the protein, but may
lead to new therapies for heart muscle damage. The research appeared in the
June 15 edition of the scientific journal Genes & Development.

The protein, MCL1, is currently the focus of widespread cancer drug
development efforts. MCL1 is best known as an inhibitor of death via the
cell's suicide pathway in a process called apoptosis. The protein is elevated
in a variety of cancers, and a number of MCL1 inhibitors are in the cancer
drug development pipeline worldwide. The protein has also been linked to drug
resistance in cancer patients. Until now, however, MCL1's role in heart muscle
cells was unclear.

"Our study shows that MCL1 is required for normal cardiac function and that
the protein may be critical in protecting the heart from apoptosis," said
Joseph Opferman, Ph.D., an associate member of the St. Jude Department of
Biochemistry and the paper's corresponding author. Unlike skin or blood cells,
heart muscle cells cannot be replaced, so even a small loss through apoptosis
can be devastating. In this study, knocking out MCL1 in mice led to death from
cardiomyopathy within weeks.

"These findings suggest that cancer-related drug development efforts should
focus on reducing MCL1 expression in target cells rather than eliminating the
protein's function completely," Opferman said.

The results also have implications for treating heart muscle damage following
heart attacks or other insults. While limiting MCL1 in cancer cells might aid
in destroying them, providing higher levels of the protein in heart muscle
cells might benefit a patient recovering from a heart attack or other heart
damage. "These findings have broad implications for human health," Opferman

MCL1 belongs to a protein family involved in regulating apoptosis. The body
uses apoptosis to rid itself of damaged, dangerous or unneeded cells. MCL1
prevents apoptosis by blocking the activity of other members of the same
protein family that promote the process.

This research builds on previous work from Opferman's laboratory that
identified a second form of MCL1. That form works inside rather than outside
the mitochondria and helps to produce the chemical energy that fuels cells.
Mitochondria are specialized structures inside cells that serve as their power

The latest results suggest both forms of MCL1 are necessary for normal heart
function, said the paper's first author Xi Wang, a University of Tennessee
Health Science Center graduate student working in Opferman's laboratory.

When investigators knocked out the mouse version of the human MCL1 gene in the
heart and skeletal muscle of both embryonic and adult mice, the animals
rapidly developed lethal cardiomyopathy. Without MCL1, researchers found that
muscle fiber in heart muscle cells was replaced by fibrous tissue, and the
pumping ability of the animals' hearts diminished. Loss of MCL1 was also
associated with a rise in apoptosis sufficient to cause fatal heart muscle

To better understand MCL1's role in normal heart function, researchers blocked
apoptosis by deleting genes for the proteins Bak and Bax as well as MCL1. Bak
and Bax promote apoptosis. Knocking out all three genes restored normal heart
function in the mice. The animals lived longer, but mitochondria in the heart
muscle did not look or function normally. These results suggest that normal
heart function requires both forms of MCL1. "The question is whether, with
time, you would see deleterious effects from the loss of MCL1 separate from
apoptosis," Opferman said.

The other authors are Madhavi Bathina, John Lynch, Brian Koss, Christopher
Calabrese, Sharon Frase, John Schuetz and Jerold Rehg, all of St. Jude.

The research was funded in part by a grant (HL102175) from the National
Institutes of Health (NIH), a grant (CA021765) from the National Cancer
Institute (NCI) at the NIH, the National Cancer Society and ALSAC.

SOURCE St. Jude Children's Research Hospital

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