Elevated expression of vacuolar proton pump genes and cellular ph in cisplatin resistance

Murakami, Tadashi; Shibuya, Izumi; Ise, Tomoko; Chen, Zhe‐Sheng; Akiyama, Shin-ichi; Nakagawa, Masayuki; Izumi, Hiroto; Nakamura, Toshio; Matsuo, Keitaro; Yamada, Yuji; Kohno, Kimitoshi

doi:10.1002/ijc.1418

Cited by 134 publications

(114 citation statements)

References 33 publications

(38 reference statements)

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“…Endocytosis and lysosome function in CP-r cellswas also found to be significantly higher than that of the sensitive parental cells (Murakami et al, 2001).…”

Section: Discussionmentioning

confidence: 85%

Reduced endocytosis and altered lysosome function in cisplatin-resistant cell lines

Chauhan

Liang

et al. 2003

Br J Cancer

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We isolated human KB adenocarcinoma cisplatin-resistant (CP-r) cell lines with multidrug-resistance phenotypes because of reduced accumulation of cisplatin and other cytotoxic compounds such as methotrexate and heavy metals. The uptake of horseradish peroxidase (HRPO) and Texas Red dextran was decreased several-fold in KB-CP-r cells, indicating a general defect in fluid-phase endocytosis. In contrast, although EGF receptors were decreased in amount, the kinetics of EGF uptake, a marker of receptormediated endocytosis, was similar in sensitive and resistant cells. However, 40 -60% of the 125 I-EGF released into the medium after uptake into lysosomes of KB-CP-r cells was TCA precipitable as compared to only 10% released by sensitive cells. These results indicate inefficient degradation of internalised 125 I-EGF in the lysosomes of KB-CP-r cells, consistent with slower processing of cathepsin L, a lysosomal cysteine protease. Treatment of KB cells by bafilomycin A 1 , a known inhibitor of the vacuolar proton pump, mimicked the phenotype seen in KB-CP-r cells with reduced uptake of HRPO, 125 I-EGF, 14 C-carboplatin, and release of TCA precipitable 125 I-EGF. KB-CP-r cells also had less acidic lysosomes. KB-CP-r cells were crossresistant to Pseudomonas exotoxin, and Pseudomonas exotoxin-resistant KB cells were crossresistant to cisplatin. Since cells with endosomal acidification defects are known to be resistant to Pseudomonas exotoxin and blocking of endosomal acidification mimics the CP-r phenotype, we conclude that defective endosomal acidification may contribute to acquired cisplatin resistance. British Journal of Cancer (2003) Cisplatin (CP) is a component of standard treatment regimens for testicular, ovarian, bladder, cervical, head and neck and small-cell and nonsmall-cell lung cancers (Ozols and Williams, 1989;Perez, 1998). Adducts of DNA with CP induce apoptosis leading to cell death (Minn et al, 1995;Simonian et al, 1997). Intrinsic or acquired resistance of tumour cells to CP undermines its clinical effectiveness (Niedner et al, 2001). Mechanisms of resistance include decreased drug accumulation (Shen et al, 2000), changes in DNA repair proficiency (Fink et al, 1998;Zhen et al, 1992;Chu, 1994;Lai et al, 1995;Johnson et al, 1996), metallothionein (MT II) (Kelly et al, 1988;Kondo et al, 1995), glutathione-related enzymes (Moscow and Cowan, 1988;Godwin et al, 1992;Zaman et al, 1995), stress response proteins (Shen et al, 1995;Hettinga et al, 1997), proto-oncogenes or apoptosis-related genes, and cancer susceptibility genes (Fanidi et al, 1993;Lowe et al, 1993;DeFeudis et al, 1996;Husain et al, 1998;Moorehead and Singh, 2000). Protein kinases (PKs) like PKA and PKC have also been associated with CP-resistance (CP-r) and use of their specific inhibitors has been demonstrated to increase CP cytotoxicity in resistant tumour cells (Gosland et al, 1996). Recently, our laboratory (Shen et al, 2000) reported decreased energy-dependent uptake of 14 C-carboplatin by CP-r cells. Copper transporters have recently been ...

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“…Endocytosis and lysosome function in CP-r cellswas also found to be significantly higher than that of the sensitive parental cells (Murakami et al, 2001).…”

Section: Discussionmentioning

confidence: 85%

Reduced endocytosis and altered lysosome function in cisplatin-resistant cell lines

Chauhan

Liang

et al. 2003

Br J Cancer

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“…These mediums were purchased from Nissui Seiyaku (Tokyo, Japan) and contained 10% fetal bovine serum. The cisplatin-resistant KB/CP4 and P/CDP6 cells were derived from KB and PC3 cells as described previously (Murakami et al, 2001) and found to be 23-63-fold more resistant to cisplatin than their parental cells (Fujii et al, 1994). Vincristine-resistant KB/VJ300 cell derived from KB was generated as described previously (Kusaba et al, 1999).…”

Section: Cell Culturementioning

confidence: 99%

Clock and ATF4 transcription system regulates drug resistance in human cancer cell lines

et al. 2007

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The mechanisms underlying cellular drug resistance have been extensively studied, but little is known about its regulation. We have previously reported that activating transcription factor 4 (ATF4) is upregulated in cisplatinresistant cells and plays a role in cisplatin resistance. Here, we find out a novel relationship between the circadian transcription factor Clock and drug resistance. Clock drives the periodical expression of many genes that regulate hormone release, cell division, sleep-awake cycle and tumor growth. We demonstrate that ATF4 is a direct target of Clock, and that Clock is overexpressed in cisplatin-resistant cells. Furthermore, Clock expression significantly correlates with cisplatin sensitivity, and that the downregulation of either Clock or ATF4 confers sensitivity of A549 cells to cisplatin and etoposide. Notably, ATF4-overexpressing cells show multidrug resistance and marked elevation of intracellular glutathione. The microarray study reveals that genes for glutathione metabolism are generally downregulated by the knockdown of ATF4 expression. These results suggest that the Clock and ATF4 transcription system might play an important role in multidrug resistance through glutathione-dependent redox system, and also indicate that physiological potentials of Clock-controlled redox system might be important to better understand the oxidative stress-associated disorders including cancer and systemic chronotherapy.

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“…9 In brief, reverse transcription was carried out using 9 anchored primers. Twenty-four primers of 10 mer were used in a PCR with the appropriate anchored primer.…”

Section: Differential Displaymentioning

confidence: 99%

“…Prehybridization and hybridization were performed as described previously. 9 Isolation of genomic clones of MRP S11 and DNA sequencing MRP S11 cDNA was identified by mRNA differential display as a gene induced in cisplatin-treated KB cells. 9 MRP S11 genomic clones were isolated from a human placental genomic library in EMBL3 by screening with the cDNA.…”

Section: Northern Blot Analysismentioning

confidence: 99%

“…Both c-Myc and AP-1 are also activated and involved in cellular responses to cisplatin. 8 One cisplatininducible cDNA clone has been shown to encode the vacuolar H ϩ -ATPase subunit c (ATP6L), 9,10 and analysis of its expression revealed that both Sp1 and Oct1 are critical for its activation by anticancer agents. 11 In order to identify novel mechanisms involved in the DNA damage response, we have used differential display to compare gene expression between control and cisplatin-treated cells.…”

mentioning

confidence: 99%

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ZNF143 activates gene expression in response to DNA damage and binds to cisplatin‐modified DNA

Ishiguchi

Izumi

Torigoe

et al. 2004

Intl Journal of Cancer

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We have identified a cisplatin-inducible gene, the mitochondrial ribosomal protein S11 (MRP S11) gene, by means of mRNA differential display. Functional analysis of the MRP S11 promoter showed that a Staf binding site in the promoter is required for both basal promoter activity and cisplatin-inducible activity. We also found that Cisplatin is a widely used anticancer agent, and DNA damage is believed to be the main basis of the antitumor effect of cisplatin. Since cisplatin resistance is a major obstacle to the treatment of solid tumors, understanding the molecular basis of the DNA damage response and of cisplatin resistance is important for clinical protocols. Cisplatin resistance is thought to involve several mechanisms, including increased drug efflux, the presence of cellular thiols, increased nucleotide excision repair activity and decreased mismatch repair activity. [1][2][3][4] In addition, several mechanisms are thought to contribute to the DNA damage response associated with cisplatin resistance. To understand fully these molecular mechanisms, it is desirable to identify and characterize all the transcription factors that are activated by DNA damage. We have previously shown that transcription factors such as Y-box binding protein (YB-1) and the CCAAT-binding transcription factor 2 (CTF2) are overexpressed in human cancer cell lines resistant to cisplatin. 5,6 YB-1 has been shown to bind preferentially to cisplatin-modified DNA 5 and is activated by nuclear translocation and by transcriptional mechanisms. Oct1 participates in the cellular response to DNA damage, 7,8 and its induction involves posttranscriptional mechanisms. Both c-Myc and AP-1 are also activated and involved in cellular responses to cisplatin. 8 One cisplatininducible cDNA clone has been shown to encode the vacuolar H ϩ -ATPase subunit c (ATP6L), 9,10 and analysis of its expression revealed that both Sp1 and Oct1 are critical for its activation by anticancer agents. 11 In order to identify novel mechanisms involved in the DNA damage response, we have used differential display to compare gene expression between control and cisplatin-treated cells. Here, we characterize one cisplatin-inducible gene, MRP S11, whose product, MRP S11, is a component of the ribosomal small subunit and binds to 12S rRNA. 12 MRP S11 appears to have RNA binding but not DNA binding activity. We have isolated the promoter region of MRP S11 in order to identify its transcriptional activators. Functional analysis revealed a critical Staf binding site in the core of the promoter. The zinc finger transcription factor, Staf, originally identified in the frog, is involved in transcriptional regulation of snRNA type and mRNA promoters transcribed either by RNA polymerase II or III. 13 Two human homologues of Staf, ZNF 76 and ZNF 143, have been isolated. 14 Here we show that activation of the transcriptional activator ZNF 143 upregulates the transcription of MRP S11. We present evidence that ZNF 143, but not ZNF 76, is induced by DNA damage. We further demonstrate that ZN...

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Elevated expression of vacuolar proton pump genes and cellular ph in cisplatin resistance

Cited by 134 publications

References 33 publications

Reduced endocytosis and altered lysosome function in cisplatin-resistant cell lines

Reduced endocytosis and altered lysosome function in cisplatin-resistant cell lines

Clock and ATF4 transcription system regulates drug resistance in human cancer cell lines

ZNF143 activates gene expression in response to DNA damage and binds to cisplatin‐modified DNA

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