A specific network of proteins in the mitochondria of tumor cells is crucial for maintaining its function, enhancing tumor cell proliferation and migration to other organs, according to researchers at the Wistar Institute in Philadelphia. After unraveling the players involved in this process, investigators targeted individual proteins from the network, severely reducing tumor growth and their migratory ability.
The study, “The Mitochondrial Unfoldase-Peptidase Complex ClpXP Controls Bioenergetics Stress and Metastasis,” published in PLOS Biology, suggests that these proteins may be targeted in a variety of cancers, including lymphoma, to decrease cancer growth and spread.
“There’s quite a bit of interest in targeting pathways involved in mitochondria function, and we’ve identified one such pathway that may provide a ‘drugable’ target for a variety of cancers,” said first author Jae Ho Seo, Ph.D., a postdoctoral fellow in the Altieri lab at Wistar, in a press release. “Other studies have shown that it is feasible to target mitochondrial proteins in preclinical models, so disrupting the network we identified in this study could shut off key processes that lead to tumor progression.”
Mitochondria are critical players in all living organisms due to their role in energy production and initiation of normal cell death. Although how they function in cancer is still not fully known, the processes involved in mitochondria biogenesis and quality control are often upregulated in cancer, suggesting they may have an essential role in tumor expansion.
Now, researchers found that a particular protein involved in maintaining mitochondria function, called ClpP, is universally overexpressed in several cancers, including prostate, liver, lung, and breast cancer, as well as lymphoma and melanoma. In these cancers, ClpP expression was found to correlate with decreased survival.
This protein is part of a complex that controls protein folding and stability within the mitochondria, reducing oxidative stress and cellular dysfunction. Therefore, when the researchers genetically engineered mice lacking ClpP or ClpX, tumor cell proliferation and migration was significantly reduced.
“This is an example of how tumors can quickly adapt to cope with their own higher biosynthetic needs,” said Dario C. Altieri, M.D., president and CEO of the Wistar Institute, director of the Wistar Institute Cancer Center, the Robert & Penny Fox Distinguished Professor, and lead author of the study.
“Mitochondria play a crucial role in a tumor’s ability to process the energy needed to grow and spread, so identifying the mechanisms of how tumors maintain the function of mitochondria and exploit it to support abnormal cell proliferation and metastatic spread may uncover new therapeutic targets in a wide variety of cancers.”