The Role of ERK1/2 in the Progression of Anti-Androgen Resistance of mtDNA Deficient Prostate Cancer
Annual summary 15 Feb 2009-30 Apr 2012
ARKANSAS UNIV FOR MEDICAL SCIENCES LITTLE ROCK
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Characterization of the mitochondrial genomic content of normal prostatic tissue and prostate cancer tumors have revealed that the carcinogenesis of normal prostate epithelial cells to prostate cancer generates heterogeneous tumors. Within a tumor, subpopulations of cancer cells harbor mitochondria with copy numbers of the mitochondrial genome that are reduced-to-depleted, in the presence of subpopulations of cancer cells that harbor elevated copy numbers of the mitochondrial genome. In the current report, the progression of prostate cancer tumors to a high Gleason grade was noted to be associated with a reduction of the mitochondrial genome content. It is generally acknowledged that a reduction of the mitochondrial genome content in prostate cancer has biological significance, activating a mitochondrial-retrograde signal for an aggressive phenotype that includes castration resistance, defined as hormone independence andor anti-androgen resistance. The current report describes core mechanisms in a mitochondrial-retrograde signal, denoted as a mitochondrial-generated progression signal mitoGPS for the progression of PCa to the castration resistant phenotype. Briefly, it was discovered that a reduction of the mitochondrial genome content generates an increase in the cellular O2 concentration, which subsequentially elevates the cellular expression of the rate-limiting enzyme of the mevalonate pathway, HMGR. The flux in the mevalonate pathway, ultimately, generated an aberrant activation of Ras-GTPases, primarily K-Ras 4A, that signal for a diverse array of cancer progression signals, such as ERK12 and Akt. The mitoGPS was confirmed to advance PCa to a disease of castration resistant that could be attenuated with the reconstitution of the mitochondrial genome content.
- Anatomy and Physiology
- Medicine and Medical Research