BERKELEY, CA (UroToday.com) - Changes in mitochondrial genome such as mutation, deletion, and depletion are associated with cancer, and recent reports demonstrate that mitochondrial genome changes determine aggressive phenotypes of cancer. However, detailed mechanisms of how mitochondrial DNA changes induce aggressive phenotypes have not been elucidated.
In our study, we demonstrate the detailed mechanisms of how mitochondrial DNA changes induce aggressive phenotypes of prostate cancer cells as follows. Mitochondrial DNA changes induce dysfunctional respiratory function. The dysfunction reduces oxygen consumption and shifts intracellular oxygen concentration from hypoxia to normoxia. Hypoxia is known to induce proteasomal degradation of HMGCoA reductase (HMGR). Thus, the hypoxia to normoxia shift induces overexpression of HMGR, activates mevalonate pathway, and induces prenylation of Ras. This event is followed by the localization of Ras to membrane, and Ras is constitutively activated. Finally this event activates following signaling such as activation of AKT, NF-kB, and ERK, leading to an aggressive phenotype of prostate cancer. It is known that mevalonate pathway is responsible for progression to aggressive phenotype of prostate cancer since statin users show reduced frequency of metastatic prostate cancer. Our finding explains how statin users have an advantage of reduced prostate cancer death. We also showed that reduction of mitochondrial DNA content, one of the markers for mitochondrial DNA changes, is associated with aggressive phenotype of prostate cancer.
One of the biggest problems of prostate cancer is that some non-aggressive cancers can shift to aggressive metastatic cancers that need to be treated. If we can predict the patients who will show this shift in the future, we can reduce unnecessary treatment of patients. Changes in mitochondrial DNA content, intracellular oxygen concentration, HMGR expression, Ras expression, and localization, which are responsible for aggressive cancer phenotype, may be used as a marker for poor survival. Additionally, inhibition of sequences of the pathway mentioned above, by certain inhibitors, could work as a new treatment to take aggressive prostate cancer back to a non-aggressive cancer.
Written by:
Masahiro Higuchi, PhD as part of Beyond the Abstract on UroToday.com. This initiative offers a method of publishing for the professional urology community. Authors are given an opportunity to expand on the circumstances, limitations etc... of their research by referencing the published abstract.
Department of Biochemistry and Molecular Biology, University of Arkansas for Medical Sciences, Little Rock, AR, USA
Consumption of oxygen: A mitochondrial-generated progression signal of advanced cancer - Abstract
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