TY - JOUR
T1 - Pristimerin-induced uveal melanoma cell death via inhibiting PI3K/Akt/FoxO3a signalling pathway
AU - Yan, Fengxia
AU - Liao, Rifang
AU - Silva, Marta
AU - Li, Shuai
AU - Jiang, Yizhou
AU - Peng, Tangming
AU - Lazarovici, Philip
AU - Zheng, Wenhua
N1 - Publisher Copyright:
© 2020 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.
PY - 2020/6/1
Y1 - 2020/6/1
N2 - Uveal melanoma (UM) is a highly invasive intraocular malignancy with high mortality. Presently, there is no FDA-approved standard for the treatment of metastatic UM. Pristimerin is a natural quinine methide triterpenoid compound with anti-angiogenic, anti-cancer and anti-inflammatory activities. However, Pristimerin potential cytotoxic effect on UM was poorly investigated. In the present study, we found the migration and invasion of UM-1 cells were inhibited by Pristimerin which also caused a rapid increase of ROS, decreased mitochondrial membrane potential, induced the accumulation of cells in G0/G1 phase, ending with apoptotic cell death. Pristimerin inhibited Akt and FoxO3a phosphorylation and induced nuclear accumulation of FoxO3a in UM-1 cells, increased the expression of pro-apoptotic proteins Bim、p27Kip1, cleaved caspase-3, PARP and Bax, and decreased the expression of Cyclin D1 and Bcl-2. LY294002 or Akt-siRNA inhibited the PI3K/Akt/FoxO3a pathway and promoted the Pristimerin-induced apoptosis, while Pristimerin effects were partially abolished in FoxO3a knockdown UM-1 cell cultures. Taken together, present results showed that Pristimerin induced apoptotic cell death through inhibition of PI3K/Akt/FoxO3a pathway in UM-1 cells. These findings indicate that Pristimerin may be considered as a potential chemotherapeutic agent for patients with UM.
AB - Uveal melanoma (UM) is a highly invasive intraocular malignancy with high mortality. Presently, there is no FDA-approved standard for the treatment of metastatic UM. Pristimerin is a natural quinine methide triterpenoid compound with anti-angiogenic, anti-cancer and anti-inflammatory activities. However, Pristimerin potential cytotoxic effect on UM was poorly investigated. In the present study, we found the migration and invasion of UM-1 cells were inhibited by Pristimerin which also caused a rapid increase of ROS, decreased mitochondrial membrane potential, induced the accumulation of cells in G0/G1 phase, ending with apoptotic cell death. Pristimerin inhibited Akt and FoxO3a phosphorylation and induced nuclear accumulation of FoxO3a in UM-1 cells, increased the expression of pro-apoptotic proteins Bim、p27Kip1, cleaved caspase-3, PARP and Bax, and decreased the expression of Cyclin D1 and Bcl-2. LY294002 or Akt-siRNA inhibited the PI3K/Akt/FoxO3a pathway and promoted the Pristimerin-induced apoptosis, while Pristimerin effects were partially abolished in FoxO3a knockdown UM-1 cell cultures. Taken together, present results showed that Pristimerin induced apoptotic cell death through inhibition of PI3K/Akt/FoxO3a pathway in UM-1 cells. These findings indicate that Pristimerin may be considered as a potential chemotherapeutic agent for patients with UM.
KW - cell death
KW - FoxO3a
KW - nuclear accumulation
KW - Pristimerin
KW - uveal melanoma
UR - http://www.scopus.com/inward/record.url?scp=85084007566&partnerID=8YFLogxK
U2 - 10.1111/jcmm.15249
DO - 10.1111/jcmm.15249
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C2 - 32347651
AN - SCOPUS:85084007566
SN - 1582-1838
VL - 24
SP - 6208
EP - 6219
JO - Journal of Cellular and Molecular Medicine
JF - Journal of Cellular and Molecular Medicine
IS - 11
ER -