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Chandrani Chattopadhyay, Jason Roszik, Elizabeth Grimm, Scott E Woodman; Monosomy 3 uveal melanoma cells have a unique metabolic phenotype distinct from disomy 3.. Invest. Ophthalmol. Vis. Sci. 2017;58(8):2504.
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© ARVO (1962-2015); The Authors (2016-present)
Uveal melanoma (UM) is the most frequent primary intraocular cancer in adults and about 50% of primary uveal melanoma metastasize, preferentially in liver with very poor prognosis. The most important genetic alterations associated with poor prognosis in UM are BAP1 gene alterations and loss of an entire copy of Chromosome 3 (monosomy3), which are most often concurrent, BAP1 is encoded on chromosome 3. It is unknown whether monosomy 3 and Bap1 loss are independent or interdependent mechanisms.
Cell survival analysis with monosomy and disomy 3 UM cells in presence and absence of Oxidative phosphorylation (Ox Phos) inhibitor, IACS-10759, developed at UT MD Anderson Cancer Center were performed. Cells were cultured under ambient oxygen or 1% oxygen. Mitotracker Red dye staining was used to assay the extent of active mitochondria in monosomy 3 and disomy 3 cells. Other analyses to differentiate monosomy and disomy 3 cells included seahorse analysis for Ox Phos and metabolic profile analysis with mass spectrometric methods followed by Ingenuity Pathway Analysis.
Three UM cell lines with monosomy3 were more resistant to IACS-10759 when compared to three lines with normal chromosome 3 copy number. This resistance diminishes under hypoxic conditions or in galactose media, when Ox Phos is not the predominant form of sugar metabolism. Further studies show more active mitochondria and a larger mitochondrial reserve capacity in monosomy3 cells. SDHA, a key enzyme connecting the TCA cycle to mitochondrial ETC, is up regulated in monosomy 3 cells and may be responsible for the resistant phenotype.
We conclude that UM cells with monosomy3 are more resistant to mitochondrial Ox Phos inhibitor due to larger mitochondrial reserve capacity. We are now in the process of elucidating the underlying molecular basis that can account for this difference in monosomy3 containing UM cells. Genes/proteins responsible for this resistance can be developed as a target for combination therapy with the Ox Phos inhibitor, such as, IACS-10759
This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.
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