Researchers have identified a protein that seems to help keep prostate cancer cells energetic and well, increasing tumor cell proliferation and invasion, and preventing cell death mechanisms from activating. Targeting this protein, called TRAP1, may be a therapeutic approach for prostate cancer patients.
The study, “Transgenic Expression of Mitochondrial Chaperone TRAP1 Accelerates Prostate Cancer Development,” was published in the Journal of Biological Chemistry.
Mechanisms that control protein folding in mitochondria, a cell’s powerhouse, are necessary for preventing protein toxicity and promoting cellular adaptation to an unfavorable environment by modifying such energy production. These mechanisms mainly rely on chaperones that direct the refolding of misfolded proteins or, conversely, on degrading misfolded or aggregated proteins.
Studies suggest that cancer cells exploit these mechanisms to survive. Indeed, a number reported that the heat shock protein 90 (HSP90) and TRAP1, two mitochondrial chaperones, are found at higher levels in the mitochondria of cancer cells than in that of healthy cells.
Investigating the impact of TRAP1 on disease, researchers at The Wistar Institute previously engineered mice to lack TRAP1, revealing that these mice lived longer and exhibited fewer age-related diseases. This finding suggested that the molecule was involved in disease, but its exact role in cancer development was not identified.
“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,” Dario C. Altieri, MD, president and CEO of The Wistar Institute, director of The Wistar Institute Cancer Center, and the Robert & Penny Fox Distinguished Professor, said in a press release. “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.”
The researchers now sought to understand TRAP1’s role in cancer by promoting its overexpression (excessive copies) in mice that already lacked one copy of the PTEN gene. PTEN is found in 40 percent of prostate cancer cases, and the researchers believed these mice would more accurately mimic the behavior of human prostate tumors.
They found that mice with a loss of PTEN and excessive TRAP1 had markedly aggressive, early onset and invasive prostate cancer. Such outcomes, the researchers found, were caused by increased tumor cell proliferation and migration, as well as the inhibition of programmed cell death mechanisms.
These findings suggest that TRAP1 expression in the prostate maintains the mitochondrial health of tumor cells through enhanced protein folding quality control.
“What is exciting about these findings is the fact that we believe TRAP1 is a druggable target,” Altieri said. “We are continuing to advance our promising research and development program aimed at targeting the mitochondria in tumors.”