Researchers have identified a protein that plays an important role in controlling cell energy production as a driver of prostate cancer. Using mice, they show how increasing the protein, TRAP1, results in aggressive, invasive prostate cancer when there is loss of the tumor suppressor protein PTEN - as occurs in over a third of prostate cancers.
The scientists - from The Wistar Institute Cancer Center in Philadelphia, PA - report their findings in the The Journal of Biological Chemistry.
"What is exciting about these findings is the fact that we believe TRAP1 is a druggable target."
Increasingly, researchers are looking at the molecular processes that keep cells functioning and stable for clues on how cancer arises.
Of particular interest are the sophisticated mechanisms that control the structure and function - as well as the assembly, degradation, and recycling - of proteins, the workhorses that toil incessantly in and around living cells.
Collaborating networks of chaperone molecules watch over these mechanisms to ensure the overall stability or proteostasis of proteins.
The focus of the new study is a particular chaperone protein called TRAP1 that regulates proteostasis in mitochondria - the tiny compartments inside cells that create chemical units of energy for powering the cell.
TRAP1 is structurally similar to HSP90, another protein that is found in larger amounts in the mitochondria of cancer cells.
TRAP1 promotes 'mitochondrial fitness' in prostate tumors
In previous work, Prof. Altieri and colleagues had studied mice genetically engineered to lack TRAP1. The mice lived longer and had fewer age-related illnesses, suggesting TRAP1 played an important role in disease.
- In the United States, prostate cancer is the
most commonnon-skin cancer in men
- Most forms of prostate cancer grow slowly
- Most men with prostate cancer are aged over 65 and do not die from it.
Altieri explains the rationale for the new study:
"In our prior study, while we had evidence that hinted at TRAP1's role in tumor growth, we lacked the direct evidence we needed to define the role of this protein in prostate cancer development."
In the new study, the team engineered mice with an over-abundance of TRAP1, instead of mice lacking the protein.
In addition, the team bred the mice to lack a copy of the gene that codes for PTEN, a tumor suppressor protein. Around 40 percent of prostate cancers - and more aggressive tumors in particular - lack one copy of the gene. The team was trying to simulate in the mice conditions as close to human prostate cancer as possible.
The results showed that increased TRAP1 with loss of PTEN led to aggressive, early-onset, invasive prostate cancer in the mice.
Closer examination revealed increased proliferation of tumor cells, blocking of apoptosis - a type of programmed cell death thought to reduce tumor cell development - and increased epithelial cell invasion, "without changes in mitochondrial bioenergetics," the authors note.
The researchers conclude their findings suggest TRAP1 promotes "mitochondrial fitness" in prostate tumors, helping them become more aggressive and resistant to treatment. They suggest the protein could be an "actionable" therapeutic target.
"As we better understand the role of mitochondria in cancer, it's important to thoroughly study the roles of the proteins involved in helping tumors receive the energy they desire for survival."
Prof. Dario C. Altieri