Abstract:
:Many tumors are resistant to drug-induced cell-cycle arrest and apoptosis. We have reported that apoptosis can be restored in human multidrug-resistant (MDR) hepatocellular carcinoma cell lines by celecoxib. Here we show that P-glycoprotein (P-gp) mediates cell-cycle arrest and autophagy induced by celecoxib in human MDR overexpressing hepatocellular carcinoma cell line by down-regulation of the HGF/MET autocrine loop and Bcl-2 expression. Exposure of cells to a low concentration of celecoxib down-regulated the expression of mTOR and caused G1 arrest and autophagy, while higher concentration triggered apoptosis. Cell growth inhibition and autophagy were associated with up-regulation of the expression of TGFbeta1, p16(INK4b), p21(Cip1) and p27(Kip1) and down-regulation of cyclin D1, cyclin E, pRb and E2F. The role of P-glycoprotein expression in resistance of MDR cell clone to cell-cycle arrest, autophagy and apoptosis was shown in cells transfected with MDR1 small interfering RNA. These findings demonstrate that the constitutive expression of P-gp is involved in the HGF/MET autocrine loop that leads to increased expression of Bcl-2 and mTor, inhibition of eIF2alpha expression, resistance to autophagy/apoptosis and progression in the cell-cycle. Since mTor inhibitors have been proposed in treatment of "drug resistant" cancer, these data may help explain the reversing effect of mTor inhibitors.
journal_name
Biochem Pharmacoljournal_title
Biochemical pharmacologyauthors
Mazzanti R,Platini F,Bottini C,Fantappiè O,Solazzo M,Tessitore Ldoi
10.1016/j.bcp.2009.03.013subject
Has Abstractpub_date
2009-07-01 00:00:00pages
21-32issue
1eissn
0006-2952issn
1873-2968pii
S0006-2952(09)00189-0journal_volume
78pub_type
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journal_title:Biochemical pharmacology
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pub_type: 杂志文章,评审
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journal_title:Biochemical pharmacology
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journal_title:Biochemical pharmacology
pub_type: 杂志文章
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