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Prevention of Akt phosphorylation is a key to targeting cancer stem-like cells by mTOR inhibition

Abstract

CD133 expression in pancreatic cancer correlates with poor prognosis and increased metastasis. CD133+ pancreatic cancer cells exhibit cancer stem cell (CSC)-like properties. We established a CD133+ cell-rich subline from Capan-1 pancreatic cancer cells as a pancreatic CSC model and compared the effects of KU-0063794, a dual mTORC1/mTORC2 inhibitor, against those of mTORC1-specific rapamycin. We found that KU-0063794 prevents sphere formation, a self-renewal index, at high concentrations. Rapamycin inhibited sphere formation but to a lesser degree. In the present study, we aimed to determine the mechanistic roles of mTOR complex 2 (mTORC2) in maintaining CSC-like properties. By examining the PI3K/Akt/mTOR signaling pathway, we observed lower Akt phosphorylation in KU-0063794-treated cells. Phosphorylation of mTORC1 downstream effectors was inhibited by both inhibitors. Thus, mTORC2 activates Akt and modulate stem-like properties, whereas mTORC1 downstream signaling correlates directly with stem-like properties.

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Acknowledgements

We wish to thank T. Obara and Y. Miyazaki for their cooperation in a part of this study, and Y. Setogawa for her expert secretarial assistance. This work was supported by JSPS Grant-in-Aid for Scientific Research (B) Grant Number 25293288 and (C) Grant Number 26462069 from the Ministry of Education, Culture, Sports, Science and Technology, Japan.

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Correspondence to Shyuichiro Matsubara.

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Matsubara, S., Tsukasa, K., Kuwahata, T. et al. Prevention of Akt phosphorylation is a key to targeting cancer stem-like cells by mTOR inhibition. Human Cell 33, 1197–1203 (2020). https://doi.org/10.1007/s13577-020-00416-9

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  • DOI: https://doi.org/10.1007/s13577-020-00416-9

Keywords

  • Pancreatic cancer stem cells
  • CD133
  • Mechanistic/mammalian target of rapamycin (mTOR)
  • mTOR complex 1 (mTORC1)
  • mTOR complex 2 (mTORC2)