Prevention of Akt phosphorylation is a key to targeting cancer stem-like cells by mTOR inhibition
- PDF / 1,995,831 Bytes
- 7 Pages / 595.276 x 790.866 pts Page_size
- 94 Downloads / 180 Views
RESEARCH ARTICLE
Prevention of Akt phosphorylation is a key to targeting cancer stem‑like cells by mTOR inhibition Shyuichiro Matsubara1,2 · Koichiro Tsukasa1,2 · Taisaku Kuwahata1,2 · Sonshin Takao1,2,3 Received: 1 May 2020 / Accepted: 13 August 2020 © Japan Human Cell Society 2020
Abstract CD133 expression in pancreatic cancer correlates with poor prognosis and increased metastasis. C D133+ pancreatic cancer + cells exhibit cancer stem cell (CSC)-like properties. We established a C D133 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. Keywords Pancreatic cancer stem cells · CD133 · Mechanistic/mammalian target of rapamycin (mTOR) · mTOR complex 1 (mTORC1) · mTOR complex 2 (mTORC2)
Introduction Pancreatic cancer is an aggressive and fatal malignancy with a 5-year survival rate of approximately 8% [1]. Furthermore, the mortality rate continues to increase. Currently, it is the fourth leading cause of cancer-related deaths in Japan and the United States [1, 2]. The clinical course of the disease is disastrous and innovative new treatments are needed. The cancer stem cell (CSC) theory has been established and the discovery of CSCs in solid tumor types has been Electronic supplementary material The online version of this article (https://doi.org/10.1007/s13577-020-00416-9) contains supplementary material, which is available to authorized users. * Shyuichiro Matsubara [email protected]‑u.ac.jp; [email protected] 1
Division of Cancer and Regenerative Medicine, Kagoshima University Graduate School of Medical and Dental Sciences, 8‑35‑1 Sakuragaoka, Kagoshima 890‑8520, Japan
2
Center for Advanced Biomedical Science and Swine Research, Kagoshima University, 8‑35‑1 Sakuragaoka, Kagoshima 890‑8520, Japan
3
Tanegashima Medical Center, 7463, Nishino‑omote 891‑3198, Japan
reported [3–5]. CSCs have the capacity for self-renewal, and for “differentiating” into non-self-renewing bulk tumor cells [3–5]. CSCs can therefore initiate and repopulate an entire tumor. They are believed to be responsible for metastasis, and for chemical and radiation resistance. Removal of pancreatic CSCs will abolish tumor initiation and result in effective inhibition of cancer recurrence. Moreover, signal pathways maintaining CSCs are good targets for
Data Loading...
