Transfection with Protein Kinase Cα Confers Increased Multidrug Resistance to MCF-7 Cells Expressing P-Glycoprotein

Yu, Gang; Ahmad, Shakeel; Aquino, Angelo; Fairchild, Craig R.; Trepel, Jane B.; Ohno, Shigeo; Suzuki, Koichi; Tsuruo, Takashi; Cowan, Kenneth H.; Glazer, Robert I.

doi:10.3727/095535491820873263

Cited by 150 publications

(69 citation statements)

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“…Stimulation of Pgp phosphorylation by PKC activators PMA (TPA) was correlated with a decrease of drug accumulation (Bates et al, 1992;Chambers et al, 1992;Fine et al, 1988), while inhibition of Pgp phosphorylation by staurosporine, a protein kinase inhibitor, caused an increase of drug accumulation by inhibition of the drug efflux (Chambers et al, 1992;Ma et al, 1991). Furthermore, in Pgp expressing BC-19 cells transfected with PKCa, Pgp was more phosphorylated and this resulted in more resistant cells with a further decreased vinblastine accumulation compared to the cells without PKCa transfection (Yu et al, 1991). Moreover, PKC seemed to be involved in drug resistance independent of Pgp, since exposure of drug-sensitive cell lines to phorbol ester induced a drug-resistant phenotype (Takeda et al, 1991;Fine et al, 1988).…”

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confidence: 99%

“…Recently, several reports have indicated that modulators of protein kinase C (PKC) activities were able to modulate Pgp MDR (Yu et al, 1991;Bates et al, 1992;Chambers et al, 1992). Stimulation of Pgp phosphorylation by PKC activators PMA (TPA) was correlated with a decrease of drug accumulation (Bates et al, 1992;Chambers et al, 1992;Fine et al, 1988), while inhibition of Pgp phosphorylation by staurosporine, a protein kinase inhibitor, caused an increase of drug accumulation by inhibition of the drug efflux (Chambers et al, 1992;Ma et al, 1991).…”

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confidence: 99%

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Genistein modulates the decreased drug accumulation in non-P-glycoprotein mediated multidrug resistant tumour cells

Versantvoort

Schuurhuis²,

Pinedo³

et al. 1993

Br J Cancer

126

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In tumour cells the pharmacological basis for multidrug resistance (MDR) often appears to be a reduced cellular cytostatic drug accumulation caused by the drug efflux protein, P-glycoprotein (Pgp MDR), or by other drug transporters (non-Pgp MDR). Here we report the reversal of the decreased daunorubicin (DNR) accumulation in five non-Pgp MDR cell lines (GLC4/ADR, SW-1573/2R120, HT1080/DR4, MCF7/Mitox and HL60/ADR) by genistein. Genistein inhibited the enhanced DNR efflux in the GLC4/ADR cells. In these cells the decreased VP-16 accumulation was also reversed by genistein. Three other (iso)flavonoids biochanin A, apigenin and quercetin also increased the DNR accumulation in the GLC4/ADR cells. In contrast to the effects on non-Pgp MDR cells, 200 microM genistein did not increase the reduced DNR accumulation in three Pgp MDR cell lines (SW-1573/2R160, MCF7/DOX40 and KB8-5) or in the parental cell lines. In conclusion the use of genistein provides a means to probe non-Pgp related drug accumulation defects. Images Figure 1 Figure 6

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confidence: 99%

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confidence: 99%

Genistein modulates the decreased drug accumulation in non-P-glycoprotein mediated multidrug resistant tumour cells

Versantvoort

Schuurhuis²,

Pinedo³

et al. 1993

Br J Cancer

126

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“…In the cells with silencing of CtBP1 expression, inhibition of MDR1 mRNA expression (Figure 2a) was greater than that of P-gp expression (Figure 2b). This is likely due to the high content of P-gp in these cells (25)(26)(27) and the relatively long half-life (14-17 h) of the protein (28). The role for CtBP1 in the activation of MDR1 expression was demonstrated not only in the MDR cancer cell lines whose expression of MDR1/P-gp is induced by drug treatments (Figure 2a and b), but also in the cancer cells that intrinsically express MDR1/P-gp (Figure 2d).…”

Section: Discussionmentioning

confidence: 99%

Involvement of CtBP1 in the transcriptional activation of the MDR1 gene in human multidrug resistant cancer cells

Jin

Scotto

Hait

et al. 2007

Biochemical Pharmacology

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Drug resistance caused by overexpression of P-glycoprotein (P-gp), the MDR1 (ABCB1) gene product, limits the therapeutic outcome. Expression of MDR1 can be induced by divergent stimuli, and involves a number of transcriptional factors. We found that the expression of CtBP1 (C-terminalbinding protein 1), a transcriptional co-regulator, was increased (~4 -fold) in human multidrug resistant (MDR) cancer cell lines, NCI/ADR-RES and A2780/DX, as compared to their sensitive counterparts. Silencing of CtBP1 expression by RNAi decreased the MDR1 mRNA and P-gp. Knockdown of CtBP1 also enhanced the sensitivity of MDR cells to chemotherapeutic drugs that are transported by P-gp and increased intracellular drug accumulation. In a reporter gene assay, cotransfection of MDR1 promoter constructs with a CtBP1 expression vector resulted in a ~2-4-fold induction of MDR1 promoter activity. CtBP1 appeared to contribute to the activation of MDR1 transcription through directly interacting with the MDR1 promoter, as evidenced by its physical binding to the promoter region of the MDR1 gene in chromatin immunoprecipitation and electromobility shift assays. Histone modifications at the MDR1 promoter, such as monomethylation, di-methylation, and acetylation of histone H3, were not found to be affected by silencing of CtBP1 expression. Our results reveal a novel role for CtBP1 as an activator of MDR1 gene transcription, and suggest that CtBP1 might be one of the key transcription factors involved in the induction of MDR1 gene. Therefore, CtBP1 may represent a potentially new target for inhibiting drug resistance mediated by overexpression of the MDR1 gene.

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“…In DOX-resistant HL-60 cells, a non-P-gp-expressing human promyelocytic leukaemia cell line, MRP was identified primarily in the endoplasmic reticulum, with lower levels also present in the plasma membrane (Marquardt and Center, 1992;Krishnamachary and Center, 1993), whereas a predominant function as a plasma membrane efflux pump has been demonstrated in a SCLC and in a non-small-cell lung carcinoma (NSCLC) cell line selected by exposure to DOX (Zaman et al, 1994 76(1), [67][68][69][70][71][72][73][74][75][76] In the present study, an additional possible mechanism for the intrinsically resistant phenotype of LoVo/C7 cells has been examined, namely alterations of PKC isoform pattern. Increases in overall PKC expression and/or activity have been demonstrated to correlate with a MDR phenotype in a number of cell lines O'Brian et al, 1989;Dong et al, 1991;Chaudary and Roninson, 1992;Gollapudi et al, 1992), with the Ca2+-dependent isoform oc-PKC specifically implicated in this phenomenon (Yu et al, 1991;Ahmad and Glazer, 1993). In a preliminary report, we analysed the role of Ca2+-dependent PKC isoforms in LoVo/C7 cells and our findings suggested a contribution of oc-PKC to the intrinsically resistant phenotype (Dolfini et al, 1993).…”

Section: Discussionmentioning

confidence: 99%

Characterization of a clonal human colon adenocarcinoma line intrinsically resistant to doxorubicin

Dolfini

Dasdia²,

Arancia³

et al. 1997

Br J Cancer

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Summary Intrinsic low-level resistance to anti-cancer drugs is a major problem in the treatment of gastrointestinal malignancies. To address the problem presented by intrinsically resistant tumours, we have isolated two monoclonal lines from LoVo human colon adenocarcinoma cells: LoVo/C7, which is intrinsically resistant to doxorubicin (DOX); and LoVo/C5, which shows the same resistance index for DOX as the mixed parental cell population. For comparison, we have included in the study a LoVo-resistant line selected by continuous exposure to DOX and expressing a typical multidrug resistant (MDR) phenotype. In these cell lines we have studied the expression and/or activity of a number of proteins, including P-glycoprotein 170 (P-gp), multidrug resistance-associated protein (MRP), lung resistance-related protein (LRP), glutathione (GSH)-dependent enzymes and protein kinase C (PKC) isoforms, which have been implicated in anti-cancer drug resistance. Intracellular DOX distribution has been assessed by confocal microscopy. The results of the present study indicate that resistance in LoVo/C7 cells cannot be attributed to alterations in P-gp, LRP or GSH/GSH-dependent enzyme levels. Increased expression of MRP, accompanied by alterations in the subcellular distribution of DOX, has been observed in LoVo/C7 cells; changes in PKC isoform pattern have been detected in both intrinsically and pharmacologically resistant cells.

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Transfection with Protein Kinase Cα Confers Increased Multidrug Resistance to MCF-7 Cells Expressing P-Glycoprotein

Cited by 150 publications

References 0 publications

Genistein modulates the decreased drug accumulation in non-P-glycoprotein mediated multidrug resistant tumour cells

Genistein modulates the decreased drug accumulation in non-P-glycoprotein mediated multidrug resistant tumour cells

Involvement of CtBP1 in the transcriptional activation of the MDR1 gene in human multidrug resistant cancer cells

Characterization of a clonal human colon adenocarcinoma line intrinsically resistant to doxorubicin

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