PI3K/Akt inhibition modulates multidrug resistance and activates NF-κB in murine lymphoma cell lines

Garcı́a, Mariana; Alaniz, Laura; Russo, R; Álvarez, Élida; Hajos, Silvia E.

doi:10.1016/j.leukres.2008.06.010

Cited by 71 publications

(49 citation statements)

References 28 publications

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“…The relationship between PI3K/AKT signaling and some transporter proteins, such as P-gp and MRP, have recently been revealed. For example, PI3K/AKT activity, analyzed by phosphatidylinositol trisphosphate production and p-AKT expression, is higher in the resistant cell lines than in the sensitive one; and inhibition with PI3K inhibitor, Wortmannin or LY294002, promotes apoptosis in the resistant cell lines and inhibits P-gp function and drug efflux (Garcı´a et al, 2008). Our finding that LAPTM4B-35 overexpression motivates MDR, supports the concept that the ATPdependent drug efflux via P-gp is associated with antiapoptosis via activation of PI3K/AKT signaling.…”

Section: Discussionmentioning

confidence: 99%

LAPTM4B: A novel cancer-associated gene motivates multidrug resistance through efflux and activating PI3K/AKT signaling

et al. 2010

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LAPTM4B (lysosomal protein transmembrane 4 beta) is a newly identified cancer-associated gene. Both of its mRNA and the encoded LAPTM4B-35 protein are significantly upregulated with more than 70% frequency in a wide variety of cancers. The LAPTM4B-35 level in cancer is evidenced to be an independent prognostic factor and its upregulation promotes cell proliferation, migration and invasion, as well as tumorigenesis in nude mice. In contrary, knockdown of LAPTM4B-35 expression by RNA interference (RNAi) reverses all of the above malignant phenotypes. We herein reveal a new role of LAPTM4B-35 in promoting multidrug resistance of cancer cells. Upregulation of LAPTM4B-35 motivates multidrug resistance by enhancement of efflux from cancer cells of a variety of chemodrugs with variant structures and properties, including doxorubicin, paclitaxel and cisplatin through colocalization and interaction of LAPTM4B-35 with multidrug resistance (MDR) 1 (P-glycoprotein, P-gp), and also by activation of PI3K/AKT signaling pathway through interaction of PPRP motif contained in the N-terminus of LAPTM4B-35 with the p85a regulatory subunit of PI3K. The specific inhibitors of PI3K and knockdown of LAPTM4B-35 expression by RNAi eliminate the multidrug resistance effect motivated by upregulation of LAPTM4B-35. In conclusion, LAPTM4B-35 motivates multidrug resistance of cancer cells by promoting drug efflux through colocalization and interaction with P-gp, and anti-apoptosis by activating PI3K/AKT signaling. These findings provide a promising novel strategy for sensitizing chemical therapy of cancers and increasing the chemotherapeutic efficacy through knockdown LAPTM4B-35 expression by RNAi.

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Section: Discussionmentioning

confidence: 99%

LAPTM4B: A novel cancer-associated gene motivates multidrug resistance through efflux and activating PI3K/AKT signaling

et al. 2010

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“…Persistent activation of the PI3K/Akt pathway has been observed to be involved in multidrug resistance (MDR) in lymphoma cell lines, mantle lymphoma, diffuse large B-cell lymphoma (DLBCL) and T-cell lymphoma (20)(21)(22)(23). Akt has been postulated to phosphorylate >9000 proteins (24).…”

Section: Discussionmentioning

confidence: 99%

4-Chlorobenzoyl berbamine induces apoptosis and G2/M cell cycle arrest through the PI3K/Akt and NF-κB signal pathway in lymphoma cells

Shen²,

Min³

et al. 2010

Oncol Rep

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Abstract. Berbamine is an herbal compound derived fromBerberis amurensis, which is used in Chinese traditional medicine. However, few studies have investigated this antitumor effect or the underlying mechanisms of berbamine on lymphoma cells. We investigate the effect, as well as the mechanism of action, of 4-chlorobenzoyl berbamine (BBD9) on Raji, L428, Namalwa and Jurkat lymphoma cells lines. Our findings show that BBD9 inhibits cell proliferation and induces cell apoptosis in lymphoma cell lines as well as G2/M cell cycle arrest through PI3K/Akt and NF-κB signaling pathways in a caspase-dependent manner. These results may provide new insights into the treatment of lymphoma.

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Section: Abstract Background/aim: (-)-Epigallocatechin-3-gallate (Egmentioning

confidence: 99%

“…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).…”

mentioning

confidence: 99%

(–)-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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PI3K/Akt inhibition modulates multidrug resistance and activates NF-κB in murine lymphoma cell lines

Cited by 71 publications

References 28 publications

LAPTM4B: A novel cancer-associated gene motivates multidrug resistance through efflux and activating PI3K/AKT signaling

LAPTM4B: A novel cancer-associated gene motivates multidrug resistance through efflux and activating PI3K/AKT signaling

4-Chlorobenzoyl berbamine induces apoptosis and G2/M cell cycle arrest through the PI3K/Akt and NF-κB signal pathway in lymphoma cells

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

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