Involvement of heat shock factor in regulating transcriptional activation of MDR1 gene in multidrug-resistant cells

Kim, Sun‐Hee; Hur, Won-young; Kang, Chi‐Dug; Lim, Young-Soon; Kim, Dong-Wan; Chung, Byung-Seon

doi:10.1016/s0304-3835(97)04725-3

Cited by 29 publications

(15 citation statements)

References 17 publications

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“…and heat shock or sodium arsenite increase the activity of MDR1 promoter via HSEs (Miyazaki et al, 1992;Kim et al ., 1996;Kioka et al , 1992) . Recently, it has been shown that FM3A/M and P388/M MDR cells isolated in our laboratory have a constitutively activated HSF, and consequently express hsp70, hsp90 and P-gp higher than their parental cells, suggesting that activation of HSF is associated with the increased M D R 1 gene expression and HSF could be an useful target for reversing MDR (Kim et al, 1997). Therefore, it is worthwhile to examine whether MDR phenotype could be restored by inhibition of a constitutively active HSF found in MDR cells.…”

Section: Discussionmentioning

confidence: 90%

“…After 6 h transfection, cells were subjected to dimethyl sulfoxide shock for 3 min, followed by incubation for additional 40 h. Indicated concentrations of sodium arsenite and/or quercetin then were added to culture medium for the transfected cells, and CAT assay was carried out 8 h later. C AT enzymatic activity in the transfected cells was determined by thin layer chromatography as previously described (Kim et al, 1997).…”

Section: Growth Inhibition Assay and Cat Assaymentioning

confidence: 99%

“…For the electrophoretic mobility shift assay, nuclear extracts from cells were prepared as described previously (Kim et al ., 1997). Cells (2 1 0 6 ) were harvested and washed with cold phosphate buff e r e d saline and resus-pended in 50 ml of lysis buffer (10 mM HEPES, pH 7.9, 1.5 mM MgCl 2 , 10 mM KCl, 0.5 mM dithiothreitol, 0.5 mM phenylmethylsulphonyl fluoride).…”

Section: Electrophoretic Mobility Shift Assaymentioning

confidence: 99%

“…Since FM3A/M and P388/M MDR cells showed a constitutive HSF DNA-binding activity under the non-stressed condition (Kim et al, 1997) and quercetin has been shown to interfere with the formation of the complex between the HSE and HSF, and to downregulate the level of HSF1 (Hosokawa et al, 1992;Nagai et al, 1995). It was examined whether the constitutive HSF activity in MDR cells could be downregulated by quercetin.…”

Section: Effect Of Quercetin On Constitutive and Sodium Arsenite-indumentioning

confidence: 99%

“…We have previously demonstrated that MDR cells such as P388/M and FM3A/M cells showed the constitutive HSF DNA-binding activity and the concurrent increase in hsp7 0 and hsp90 in the absence of stress (Kim et al, 1997). The activation of HSF might be an important transcriptional regulator for inducing M D R 1 gene, and the overexpression of hsp70 confers resistance to at least some anticancer drugs (Kim et al, 1996;Kioka et al,1992;Karlseder et al, 1996).…”

Section: Introductionmentioning

confidence: 99%

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Suppression of multidrug resistance via inhibition of heat shock factor by quercetin in MDR cells

Kim

Yeo²,

Lim³

et al. 1998

Exp Mol Med

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M D R 1 promoter has been shown to contain heat shock elements (HSE), and it has been reported that FM3A/M and P388/M MDR cells show a constitutively activated heat shock factor (HSF), suggesting that HSF might be an important target for reversing the multidrug resistance. Therefore, it was examined whether quercetin, which has been shown to interfere with the formation of the complex between HSE and H S F, and to downregulate the level of HSF1, can sensitize MDR cells against anticancer drugs by inhibition of HSF DNA-binding activity. In this study, quercetin appeared to inhibit the constitutive HSF DNA-binding activity and the sodium arsenite-induced HSF DNA-binding activity in the MDR cells. The basal and sodium arsenite-induced MDRCAT activities were remarkably suppressed by the treatment of quercetin. These results were well consistent with the finding that the treatment of quercetin decreased the expression level of P-gp, M D R 1 gene product, in dosedependent manner, and markedly increased the sensitivity of MDR cells to vincristine or vinblastine. These results suggest that quercetin can decrease the expression of P-gp via inhibition of HSF DNAbinding activity, and might be useful as a chemosensitizer in MDR cells.

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Section: Discussionmentioning

confidence: 90%

Section: Growth Inhibition Assay and Cat Assaymentioning

confidence: 99%

Section: Electrophoretic Mobility Shift Assaymentioning

confidence: 99%

Section: Effect Of Quercetin On Constitutive and Sodium Arsenite-indumentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Suppression of multidrug resistance via inhibition of heat shock factor by quercetin in MDR cells

Kim

Yeo²,

Lim³

et al. 1998

Exp Mol Med

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Hyperthermia for treatment of rectal cancer: Evaluation for induction of multidrug resistance gene (mdr1) expression

Stein¹,

Rau²,

Wust³

et al. 1999

Int. J. Cancer

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Environmental stress factors, such as heat, may induce multidrug resistance gene (mdr1) expression, which could result in the disadvantageous multidrug resistance (MDR) phenotype. To evaluate this possibility in a clinical situation, we investigated mdr1 gene expression in patients with locally advanced rectal cancer who underwent preoperative radio‐chemo‐thermo‐therapy (RCTT). Patients were classified into groups according to the treatment schedule of RCTT vs. radio‐chemo‐therapy (RCT) without hyperthermia (control group). Expression of the mdr1 gene was analyzed in tumors and normal rectal tissues prior to and post‐treatment (RCTT or RCT, respectively) by means of semi‐quantitative and quantitative reverse transcription‐polymerase chain reaction (RT‐PCR). The data were correlated with therapeutic response and survival parameters. Based on our evaluation criteria, in 2 of 19 tumors of the RCTT group, mdr1 gene expression was increased more than 2‐fold; in 3 of 19 tumors of this group, however, mdr1 expression was decreased more than 2‐fold. In the patient control group, levels of mdr1 gene expression were reduced in 2 of 8 tumors. Thus, hyperthermia combined with RCT (RCTT) in comparison with RCT alone does not lead to an increase in mdr1 gene expression in patients with locally advanced rectal cancer within the preoperative treatment schedule. The risk of inducing the classical multidrug resistance phenotype by hyperthermia was thus minimal in this clinical setting. Subsequent adjuvant chemotherapy should thus not be hindered. Int. J. Cancer 80:5–12, 1999. © 1999 Wiley‐Liss, Inc.

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Use of the human MDR1 promoter for heat‐inducible expression of therapeutic genes

Walther¹,

Stein²,

Schlag³

2001

Intl Journal of Cancer

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The promoter of the human multidrug resistance gene (mdr1) harbors stress-responsive elements, which can be induced e.g., by heat or cytostatic drugs. In previous studies the drug-responsiveness of the mdr1 promoter was successfully used for the drug-inducible expression of the human TNF-␣ gene in vitro and in vivo. Beside the drug-responsive elements of the mdr1 promoter, heat-shock responsive elements have also been identified, which could be exploited for construction of heat-inducible expression vectors. To analyze the hyperthermia-inducibility of the mdr1 promoter we used the pmdr-p-CAT and pM3mdr-p-hTNF vector constructs. Both constructs carry the mdr1 promoter fragment spanning from ؊207 to ؉153 to drive expression of the CAT-reporter or TNF-␣ gene. We tested the heat-induced CAT-reporter and TNF-␣ expression in vitro in transduced HCT15 and HCT116 human colon carcinoma cells. For the studies the transduced tumor cells were treated with hyperthermia at 41.5°C or 43°C for 2 hr to induce CAT or TNF-␣ expression. Cells and supernatants were harvested before hyperthermia and at certain time points (0 -120 hr) after heat shock. The heatinduced CAT-reporter expression or TNF-␣ secretion was determined by specific ELISA. The experiments indicate that hyperthermia activates the mdr1 promoter in a temperature and time dependent manner. This induction leads to an 2-to 4-fold increase in CAT-reporter or 2-to 7-fold increase in TNF␣ expression in the tumor cell lines. These experiments reveal that the mdr1 promoter driven expression of therapeutic genes can be employed for combined cancer gene therapy approaches. © 2002 Wiley-Liss, Inc. Key words: hyperthermia; mdr1 promoter; gene therapy; cancerApart from great efforts for the improvement of expression efficiencies and targeting of vector systems in gene therapy, numerous studies are focused on the establishment of inducible vectors that are regulatable by different factors or agents. 1,2 Such vectors are useful tools for the conditional expression of therapeutic genes in tumor cells. Their attractiveness is based on the inducibility of therapeutic gene expression by modalities that are parts of cancer treatment, such as radiotherapy, chemotherapy or hyperthermia. This approach has been successfully employed for the regulated expression of cytokine genes or suicide genes for improved cancer treatment. [3][4][5] The use of therapeutic modalities for the control of gene expression combines advantages of conventional therapies (chemotherapy, radiation, hyperthermia) and gene therapy and can result in considerable improvement of therapeutic efficacy.Hyperthermia is used in combination with chemo-and radiotherapy for the improvement in the treatment of cancer. This therapeutic modality is gaining growing acceptance and is used in therapeutic settings of treatment for breast or colorectal carcinomas with varying success. 6 -8 From preclinical studies it is known that hyperthermia can sensitize tumor cells toward radiation and chemotherapy leading to improved therapeutic e...

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Involvement of heat shock factor in regulating transcriptional activation of MDR1 gene in multidrug-resistant cells

Cited by 29 publications

References 17 publications

Suppression of multidrug resistance via inhibition of heat shock factor by quercetin in MDR cells

Suppression of multidrug resistance via inhibition of heat shock factor by quercetin in MDR cells

Hyperthermia for treatment of rectal cancer: Evaluation for induction of multidrug resistance gene (mdr1) expression

Use of the human MDR1 promoter for heat‐inducible expression of therapeutic genes

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