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Poster Display session 1

1615 - Adaption of Pancreatic Cancer Cells to AKT1 Inhibition Induces the Acquisition of Cancer Stem-Cell Like Phenotype Through Upregulation of Mitochondrial Functions

Date

28 Sep 2019

Session

Poster Display session 1

Presenters

Hugo Arasanz

Citation

Annals of Oncology (2019) 30 (suppl_5): v1-v24. 10.1093/annonc/mdz238

Authors

H. Arasanz1, M. Zuazo2, E. Santamaría3, A.I. Bocanegra2, M. Gato-Cañas4, G. Fernández-Hinojal1, C. Hernández-Saez2, J. Fernández-Irigoyen5, E. Santamaria5, C. Rodríguez-Ortigosa3, G. Kochan2, R. Vera1, D. Escors2

Author affiliations

  • 1 Medical Oncology, Complejo Hospitalario de Navarra, 31008 - Pamplona/ES
  • 2 Immunomodulation-oncology, Navarrabiomed, 31008 - Pamplona/ES
  • 3 Hepatology, Centro de Investigación Médica Aplicada, Pamplona/ES
  • 4 Av. De Pío Xii, 55, Centro de Investigación Médica Aplicada, Pamplona/ES
  • 5 Proteomics Groups, Navarrabiomed, 31008 - Pamplona/ES
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Resources

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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