Downregulation of JNK/SAPK Activity Is Associated with the Cross-Resistance to P-Glycoprotein-Unrelated Drugs in Multidrug-Resistant FM3A/M Cells Overexpressing P-Glycoprotein

Kang, Chi‐Dug; Ahn, Byung-Kwon; Jeong, Choon Sik; Kim, Kwang-Woon; Lee, Heon-Jin; Yoo, Seok-Dong; Chung, Byung-Seon; Kim, Sun‐Hee

doi:10.1006/excr.2000.4807

Cited by 30 publications

(22 citation statements)

References 53 publications

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“…In corroboration with these results, it has been previously shown that P-glycoprotein overexpressing mouse mammary carcinoma cells displayed significantly lower basal as well as drug-stimulated JNK activities. 37 Comparably, the ERK1,2 inhibitor UO126 induced upregulation of P-glycoprotein as well as HIF-1␣ under control conditions that was even more increased under conditions of hyperthermia. These results point towards the notion that inactivation of JNK as well as ERK1,2 are a prerequisite for the induction of a MDR phenotype in multicellular prostate tumor spheroids and that active JNK as well as ERK1,2 may be involved in negative regulation the mdr-1 and HIF-1 genes.…”

Section: Figure 11mentioning

confidence: 95%

“…36 Downregulation of JNK was demonstrated to confer a P-glycoprotein-mediated MDR phenotype. 37 However, other studies reported on a more highly activated form of JNK in MDR cells overexpressing P-glycoprotein. 38 Recently it has been shown that the P-glycoprotein-mediated MDR phenotype is associated with increased levels of p38 MAPK.…”

Section: Effects Of Mapk Inhibitors On Hyperthermia-induced Hif-1␣ Anmentioning

confidence: 98%

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Regulation of the multidrug resistance transporter P‐glycoprotein in multicellular prostate tumor spheroids by hyperthermia and reactive oxygen species

Wartenberg

Gronczynska

Bekhite

et al. 2004

Intl Journal of Cancer

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Hyperthermia is an important component of many cancer treatment protocols. In our study the regulation of the multidrug resistance (MDR) transporter P-glycoprotein by hyperthermia was studied in multicellular prostate tumor spheroids. Hyperthermia treatment of small (50 -100 m) tumor spheroids significantly increased P-glycoprotein and mdr-1 mRNA expression with a maximum effect at 42°C, whereas only moderate elevation of P-glycoprotein was found in large (350 -450 m) tumor spheroids. Hyperthermia caused an elevation of intracellular reactive oxygen species (ROS). Inhibition of ROS generation with NADPH-oxidase inhibitors diphenylen iodonium (DPI) and 4-(2-aminoethyl)benzenesulfonyl fluoride (AEBSF) abolished P-glycoprotein expression but did not affect its transcript levels following heat treatment. This indicates that P-glycoprotein levels are controlled by regulating its translation rate or stability. Hyperthermia incubation resulted in a differential activation of p38 mitogen-activated protein kinase (MAPK), extracellular regulated kinase 1,2 (ERK1,2), and c-jun N-terminal kinase (JNK) immediately, 4 hr and 24 hr after treatment. Furthermore, upregulation of hypoxia-inducible factor 1␣ (HIF-1␣) was observed. Elevation of HIF-1␣ and Pglycoprotein expression following hyperthermia treatment were abolished upon coadministration of the p38 inhibitor SB203580. In contrast the JNK inhibitor SP600125 and the ERK1,2 inhibitor UO126 resulted in increase of HIF-1␣ and P-glycoprotein in the control as well as the hyperthermia-treated samples, indicating negative regulation of intrinsic HIF-1␣ and P-glycoprotein expression by ERK1,2 and JNK signaling cascades. In summary our data demonstrate that hyperthermia-induced upregulation of P-glycoprotein and HIF-1␣ is mediated by activation of p38, whereas ERK1,2 and JNK are involved in repression of P-glycoprotein and HIF-1␣ under control conditions. Key words: multidrug resistance; P-glycoprotein; hyperthermia; hypoxia-inducible factor 1-␣ Hyperthermia in combination with chemotherapy and radiotherapy has been previously successfully used in anti-cancer strategies. [1][2][3][4][5] The efficiency of chemotherapeutic as well as radiotherapeutic cancer treatment is generally restricted by the expression of MDR transporters that confer resistance to a variety of structurally unrelated, clinically important antineoplastic agents. 6 -8 The most clinically significant MDR transporter P-glycoprotein, a 170 kDa ATP-dependent membrane-bound transporter, has been recently demonstrated to be upregulated by hyperthermia. 9,10 The promotor of the mdr-1 gene, which encodes for P-glycoprotein, harbors different responsive elements that are inducible by various stress factors including hyperthermia. 11 In this respect, it has been previously demonstrated in colon cancer cells that hyperthermia resulted in nuclear translocation of the Y-box transcription factor YB-1 and enhanced expression of mdr-1. 12 Binding of hyperthermia factors to defined heat shock element (HSE) motifs of the mdr-1 pr...

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Section: Figure 11mentioning

confidence: 95%

Section: Effects Of Mapk Inhibitors On Hyperthermia-induced Hif-1␣ Anmentioning

confidence: 98%

Regulation of the multidrug resistance transporter P‐glycoprotein in multicellular prostate tumor spheroids by hyperthermia and reactive oxygen species

Wartenberg

Gronczynska

Bekhite

et al. 2004

Intl Journal of Cancer

View full text Add to dashboard Cite

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“…Our findings are in line with previous reports in solid cancer cell lines which showed defective JNK response to chemotherapy in P-gP( þ ) multidrug-resistant mouse mammary carcinoma cells and in DOX-resistant breast cancer cells. 16,17 However, in these studies one can not exclude that these results arise from insufficient intracellular drug to trigger JNK activation due to drug efflux by P-gP. We show here that the inability of the U937R AML cells to activate JNK was seen though the drug was accumulated intracellularly, indicating that the JNK-activation failure of anthracycline-resistant AML cells is an intrinsic characteristic of these cells.…”

Section: Discussionmentioning

confidence: 69%

“…Indeed, studies in solid tumours have associated drug resistance with intrinsic failure of the cells to activate JNK. [15][16][17][18] Whether chemoresistance in AML is attributed to JNK activation failure is not examined yet.…”

Section: Introductionmentioning

confidence: 99%

c-Jun N-terminal kinase activation failure is a new mechanism of anthracycline resistance in acute myeloid leukemia

et al. 2008

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“…The development of broad-spectrum drug resistance is often characterized by overexpression of the transmembrane efflux pump, P-glycoprotein, which is encoded by the multidrug resistance-1 (MDR1) gene, or of the MDR-associated proteins (19)(20)(21). Additionally, alterations of microtubule proteins are thought to be associated with resistance to antimicrotubule drugs and altered expression of several h-tubulin isotypes in drugresistant cells has been reported in many cases (8,18,(22)(23)(24).…”

Section: Introductionmentioning

confidence: 99%

Regulation of Class II β-Tubulin Expression by Tumor Suppressor p53 Protein in Mouse Melanoma Cells in Response toVincaAlkaloid

Arai

Matsumoto

Nagashima

et al. 2006

Molecular Cancer Research

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The continuous exposure of antimicrotubule drugs to tumors often results in the emergence of drug-resistant tumor cells with altered expression of several B-tubulin isotypes. We found that Vinca alkaloid enhanced expression of class II B-tubulin isotype (mTUBB2) in mouse B16F10 melanoma cells via alteration of the tumor suppressor p53 protein. Vincristine treatment stimulated an increase in mTUBB2 mRNA expression and promoted accumulation of this isotype around the nuclei. Transient transfection assays employing a reporter construct, together with site-directed mutagenesis studies, suggested that the p53-binding site found in the first intron was a critical region for mTUBB2 expression. Electrophoretic mobility shift assay and associated antibody supershift experiments showed that vincristine promoted release of p53 protein from the binding site. In addition, exogenous induction of TAp63; (p51A), a homologue of p53, canceled the effect of vincristine on mTUBB2 expression. These results suggest that p53 protein may function as a suppressor of mTUBB2 expression and vincristine-mediated inhibition of p53 binding results in enhanced mTUBB2 expression. This phenomenon could be related with the emergence of drug-resistant tumor cells induced by Vinca alkaloid and may participate in determining the fate of these cells.

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Downregulation of JNK/SAPK Activity Is Associated with the Cross-Resistance to P-Glycoprotein-Unrelated Drugs in Multidrug-Resistant FM3A/M Cells Overexpressing P-Glycoprotein

Cited by 30 publications

References 53 publications

Regulation of the multidrug resistance transporter P‐glycoprotein in multicellular prostate tumor spheroids by hyperthermia and reactive oxygen species

Regulation of the multidrug resistance transporter P‐glycoprotein in multicellular prostate tumor spheroids by hyperthermia and reactive oxygen species

c-Jun N-terminal kinase activation failure is a new mechanism of anthracycline resistance in acute myeloid leukemia

Regulation of Class II β-Tubulin Expression by Tumor Suppressor p53 Protein in Mouse Melanoma Cells in Response toVincaAlkaloid

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