Abstract 1615
Background
AKT/PKB is a protein kinase that plays a key role in pancreatic adenocarcinoma. Three isoforms with a similar structure but non-overlapping functions have been described: AKT1/PKBα, AKT2/PKBβ and AKT3/PKBγ. Our project studies the molecular routes of adaption to single AKT isoform silencing.
Methods
We have individually silenced AKT isoforms using short hairpin RNAs (shRNAs) delivered by lentivirus. A shRNA against an irrelevant gene was used as control. When cells adapted to the modification, high-throughput quantitative proteomics analyses were performed to evaluate the differentially altered molecular routes. Mitochondrial protein expression was determined by Western Blot. Mitochondrial function was evaluated using Agilent SeaHorse XF. Cancer stem-cell like phenotype was determined by CD44 and EpCAM expression. A subsequent silencing of the escape routes discovered was performed.
Results
Only cells adapted to AKT1 silencing, but not AKT2 or AKT3, exhibited a cancer stem-cell like phenotype with a sharp increase in CD44/EpCAM expression compared to the other cell lines or control (p < 0.0001). shAKT1 expressing cells presented a potentiation of mitochondrial functions determined both by quantitative proteomics, and by basal and maximal oxygen consumption rate (p < 0.0001). Double silencing of AKT1 and the mitochondrial protein TFB2M caused a prolonged cell growth arrest.
Conclusions
When exposed to stable AKT1 inhibition, pancreatic adenocarcinoma cells adapt by switching their metabolism from glycolysis to mitochondrial respiratorion, which suggests a reversion of Warburg effect, and adopting cancer stem-cell like phenotype. Cancer stem cells have been proposed as one of the main factors favouring therapy resistance. Targeting mitochondrial metabolism might improve the efficacy of conventional treatments.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
Grupo de Inmunomodulación.
Funding
Grupo de Inmunomodulación.
Disclosure
All authors have declared no conflicts of interest.
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