Lab scientists at the University of Pittsburgh Cancer Institute and UP's Center for Biologic Imaging have recently published an important paper in the Journal of Cell Science that sheds light on a novel method of interrupting mitosis in a cell by effectively depriving its mitochondria of a key protein. The resulting replication stress means cancer cells are stopped from successfully multiplying. Colorful images of the targeted cells actually show them stuck in anaphase trying to divide and subsequently tearing themselves apart. By identifying a compound that carries out this protein interference and disrupts normal mitochondrial fission, researchers have identified a promising therapeutic avenue for halting cancer growth.
[Cover photo on the February issue of the Journal of Cell Science shows the cell disruption process, courtesy of the Center for Biologic Imaging]
The protein is called Drp1, the compound is Mdivi-1, and the Pitt investigators working on this cancer research project are members of the lab of molecular oncologist Bennett Van Houten. The Van Houten Lab group in the Department of Pharmacology and Chemical Biology studies the structure and function of DNA repair enzymes, the global responses to stress and the consequences of mitochondrial DNA damage. Interestingly, in the process of observing the Mdivi-1 compound's effect on the activity of Drp1, they discovered that it does not actually deprive cancer cells of the necessary protein, but uses another, previously unknown mechanism to accomplish a similar result. According to Van Houten in a UPMC news release:
"To me, that’s the serendipity of science, and it’s really exciting. We were on the hunt for a drug that could make cancer cells deficient in Drp1 and, instead, we found a new cancer therapy that seems to work really well.”
Part of the experiment included pairing Mdivi-1 with a known and well-used cancer drug called cisplatin in laboratory tests. The combination was especially effective in inducing widespread, rapid cell death. Van Houten plans to move this drug combination testing into clinical trials as soon as possible. The research leading up to this point was supported by Pennsylvania Department of Health and four NIH grants. Lead author of the study just published is Van Houten lab post doc Wei Qian, Ph.D. Other Pitt team members include: Serah Choi, Gregory A. Gibson, Christopher J. Bakkenist, and Simon Watkins, who used a confocal microscope in the imaging lab to take the illuminating cell photos. The Houten Lab is located in the Hillman Cancer Center building at UPMC.
A Pdf of the article, Mitochondrial hyperfusion induced by loss of the fission protein Drp1 causes ATM-dependent G2/M arrest and aneuploidy through DNA replication stress, is available here.
[Photo courtesy of the UPMC Cancer Center]
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