The Effect of Doxorubicin on MEK-ERK Signaling Predicts Its Efficacy in HCC

Choi, Jennifer; Yip-Schneider, Michele; Albertin, Faith; Wiesenauer, Chad; Wang, Yufang; Schmidt, C. Max

doi:10.1016/j.jss.2008.01.029

Cited by 37 publications

(31 citation statements)

References 22 publications

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“…This phenomenon may indicate that MDR1 mRNA overexpression is not enough for inducing P-gp overexpression through the activation of PI3K/Akt. It has already been reported an increase in phospho-ERK levels in DOX-treated HepG2 cells (33). In this study, we also showed that DOX induced activation of MEK/ERK pathway in HepG2 cells and that U0126, a MEK/ERK inhibitor, inhibited P-gp overexpression ( Figure 5) and MDR1 mRNA ( Figure 2C).…”

Section: Effects Of a Combination Of Ly294002 With U0126 On Pglycoprosupporting

confidence: 83%

(–)-Epigallocatechin-3-gallate Down-regulates Doxorubicin-induced Overexpression of P-glycoprotein Τhrough the Coordinate Inhibition of PI3K/Akt and MEK/ERK Signaling Pathways

Satonaka

Ishida

Takai

et al. 2017

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Abstract. Background/Aim: (-)-Epigallocatechin-3-gallate (EGCG) has been indicated to regulate the function of Pglycoprotein (P-gp), which is a drug transporter encoded by the MDR1 (ABCB1) gene. P-gp expression is induced by doxorubicin (DOX). We aimed to clarify the mechanisms and inhibitory effects of EGCG on DOX-induced P-gp expression in HepG2 cells. Materials and Methods: Rhodamine 123 (Rho123) was used for P-gp substrate. Western blotting and polymerase chain reactions (PCRs) were conducted using specific antibodies and primer sets. Results: The DOXpretreated cells accumulated a significantly decreased amount of Rho123), than control cells; however, the cells pretreated with EGCG and DOX, in combination, accumulated Rho123 more than DOX-pretreated cells. DOX induced the overexpression of MDR1 mRNA and increased the phosphorylation of Akt, ERK1/2, p38 MAPK and JNK. EGCG significantly inhibited the phosphorylation of Akt and ERK. The DOX-induced P-gp overexpression was partially suppressed by an inhibitor of MEK1/2 (U0126), but not by a PI3K inhibitor (LY294002). Interestingly, the expression of P-gp was synergistically inhibited by combined treatment of U0126 with LY294002 and also inhibited by an mTORC1 inhibitor, rapamycin. Conclusion: EGCG inhibited DOX-induced overexpression of P-gp through the coordinate inhibitory action on MEK/ERK and PI3K/Akt signaling pathways.(-)-Epigallocatechin gallate (EGCG) is the most abundant component of tea polyphenols having various profitable properties, including anti-oxidative activity and cancerpreventive effect (1). In addition, concerning antitumor drug resistance, EGCG has been shown to decrease doxorubicin (DOX) resistance in a human carcinoma xenograft model mice (2) and inhibit the transport function of P-glycoprotein (P-gp), an export drug transporter causing antitumor multidrug resistance (MDR) in tumor cells (3)(4)(5).Human P-gp is a plasma membrane protein of 170 kDa encoded by the MDR1 (ABCB1) gene. The expression of MDR1 gene and P-gp is affected by various chemical substances and physico-chemical stress (5-7). We have previously suggested that the P-gp level was up-regulated through the activation of protein kinase C/nuclear factor-ĸB (PKC/NF-ĸB) in rats with streptozotocin-induced diabetes (8). Further, the expression of MDR1 gene has been also shown to be induced by PI3K/Akt/NF-ĸB signaling (9,10).EGCG has been shown to activate ERK and PI3K/Akt signaling and induce antioxidant enzymes in human mammary epithelial cells (11). Contrarily, it has been shown that EGCG inhibits the PI3K/Akt system in fibroblast cells (12) and the phosphorylation of ERK and Akt kinases in epidermal growth factor (EGF)-stimulated cells (13). More recently, accumulating evidence indicates that EGCG can inhibit PI3K/Akt and MAPK signaling systems (14)(15)(16)(17).From these backgrounds, in the present study, we aimed to clarify whether EGCG could suppress MDR and inhibit the induction of P-gp overexpression by DOX through inhibition of PI3K/Akt and ERK/MAPK signal transduction s...

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Section: Effects Of a Combination Of Ly294002 With U0126 On Pglycoprosupporting

confidence: 83%

(–)-Epigallocatechin-3-gallate Down-regulates Doxorubicin-induced Overexpression of P-glycoprotein Τhrough the Coordinate Inhibition of PI3K/Akt and MEK/ERK Signaling Pathways

Satonaka

Ishida

Takai

et al. 2017

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“…It promotes HCC tumor cell growth and it is frequently activated in HCC. It has also been shown to be activated by doxorubicin [90], serving as a tumor cell response that counters doxorubicin-induced toxicity. Direct inhibition of ERK activity increases doxorubicin sensitivity in HCC cells by inhibiting cell proliferation and promoting apoptosis [90].…”

Section: Molecular Mechanisms Of Doxorubicin Resistancementioning

confidence: 99%

Mechanisms of doxorubicin resistance in hepatocellular carcinoma

2015

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Hepatocellular carcinoma, one of the most common solid tumors worldwide, is poorly responsive to available chemotherapeutic approaches. While systemic chemotherapy is of limited benefit, intra-arterial delivery of doxorubicin to the tumor frequently produces tumor shrinkage. Its utility is limited, in part, by the frequent emergence of doxorubicin resistance. The mechanisms of this resistance include increased expression of multidrug resistance efflux pumps, alterations of the drug target, topoisomerase, and modulation of programmed cell death pathways. Many of these effects result from changes in miRNA expression and are particularly prominent in tumor cells with a stem cell phenotype. This review will summarize the current knowledge on the mechanisms of doxorubicin resistance of hepatocellular carcinoma and the potential for approaches toward therapeutic chemosensitization.

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“…Indeed, Wiesenauer et al have shown that the inhibition of ERK phosphorylation and the growth suppression by ERK specific inhibitors PD098059 and U0126 are more profound in HepG2 than in Hep3B (Wiesenauer et al 2004;Choi et al 2008). However, the decrease in ERK protein expression by antisense knockdown is more sensitive and the ?…”

Section: Ras/raf/mek/erk Pathwaymentioning

confidence: 99%

“…However, the decrease in ERK protein expression by antisense knockdown is more sensitive and the ? : p53-dependent; -: p53-independent; NA: no direct evidence available (Choi et al 2008). …”

Section: Ras/raf/mek/erk Pathwaymentioning

confidence: 99%

Distinctive pharmacological differences between liver cancer cell lines HepG2 and Hep3B

et al. 2014

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As cellular models for in vitro liver cancer and toxicity studies, HepG2 and Hep3B are the two most frequently used liver cancer cell lines. Because of their similarities they are often treated as the same in experimental studies. However, there are many differences that have been largely over-sighted or ignored between them. In this review, we summarize the differences between HepG2 and Hep3B cell lines that can be found in the literature based on PubMed search. We particularly focus on the differential gene expression, differential drug responses (chemosensitivity, cell cycle and growth inhibition, and gene induction), signaling pathways associated with these differences, as well as the factors in governing these differences between HepG2 and Hep3B cell lines. Based on our analyses of the available data, we suggest that neither HBx nor p53 may be the crucial factor to determine the differences between HepG2 and Hep3B cell lines although HBx regulates the expression of the majority of genes that are differentially expressed between HepG2 and Hep3B. Instead, the different maturation stages in cancer development of the original specimen between HepG2 and Hep3B may be responsible for the differences between them. This review provides insight into the molecular mechanisms underlying the differences between HepG2 and Hep3B and help investigators especially the beginners in the areas of liver cancer research and drug metabolism to fully understand, and thus better use and interpret the data from these two cell lines in their studies.

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The Effect of Doxorubicin on MEK-ERK Signaling Predicts Its Efficacy in HCC

Cited by 37 publications

References 22 publications

(–)-Epigallocatechin-3-gallate Down-regulates Doxorubicin-induced Overexpression of P-glycoprotein Τhrough the Coordinate Inhibition of PI3K/Akt and MEK/ERK Signaling Pathways

(–)-Epigallocatechin-3-gallate Down-regulates Doxorubicin-induced Overexpression of P-glycoprotein Τhrough the Coordinate Inhibition of PI3K/Akt and MEK/ERK Signaling Pathways

Mechanisms of doxorubicin resistance in hepatocellular carcinoma

Distinctive pharmacological differences between liver cancer cell lines HepG2 and Hep3B

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