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Inhibition of Orai1-mediated Ca 2+ entry enhances chemosensitivity of HepG2 hepatocarcinoma cells to 5-fluorouracil
Increasing evidence supports that activation of store-operated Ca entry (SOCE) is implicated in the chemoresistance of cancer cells subjected to chemotherapy. However, the molecular mechanisms underlying chemoresistance are not well understood. In this study, we aim to investigate whether 5-FU induc...
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Published in: | Journal of cellular and molecular medicine 2017-05, Vol.21 (5), p.904-915 |
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Main Authors: | , , , , , , , , , |
Format: | Article |
Language: | English |
Subjects: | |
Citations: | Items that this one cites Items that cite this one |
Online Access: | Get full text |
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Summary: | Increasing evidence supports that activation of store-operated Ca
entry (SOCE) is implicated in the chemoresistance of cancer cells subjected to chemotherapy. However, the molecular mechanisms underlying chemoresistance are not well understood. In this study, we aim to investigate whether 5-FU induces hepatocarcinoma cell death through regulating Ca
-dependent autophagy. [Ca
]
was measured using fura2/AM dye. Protein expression was determined by Western blotting and immunohistochemistry. We found that 5-fluorouracil (5-FU) induced autophagic cell death in HepG2 hepatocarcinoma cells by inhibiting PI3K/AKT/mTOR pathway. Orai1 expression was obviously elevated in hepatocarcinoma tissues. 5-FU treatment decreased SOCE and Orai1 expressions, but had no effects on Stim1 and TRPC1 expressions. Knockdown of Orai1 or pharmacological inhibition of SOCE enhanced 5-FU-induced inhibition of PI3K/AKT/mTOR pathway and potentiated 5-FU-activated autophagic cell death. On the contrary, ectopic overexpression of Orai1 antagonizes 5-FU-induced autophagy and cell death. Our findings provide convincing evidence to show that Orai1 expression is increased in hepatocarcinoma tissues. 5-FU can induce autophagic cell death in HepG2 hepatocarcinoma cells through inhibition of SOCE via decreasing Orai1 expression. These findings suggest that Orai1 expression is a predictor of 5-FU sensitivity for hepatocarcinoma treatment and blockade of Orai1-mediated Ca
entry may be a promising strategy to sensitize hepatocarcinoma cells to 5-FU treatment. |
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ISSN: | 1582-1838 1582-4934 |
DOI: | 10.1111/jcmm.13029 |