Copper-Transporting P-Type ATPase, ATP7A, Confers Multidrug Resistance and Its Expression Is Related to Resistance to SN-38 in Clinical Colon Cancer

Owatari, Satsuki; Akune, Satoshi; Komatsu, Masaharu; Ikeda, Ryuji; Firth, Sonja; Che, Xiaofang; Yamamoto, Masayuki; Tsujikawa, Kazutake; Kitazono, Masaki; Ishizawa, Takashi; Takeuchi, Tōru; Aikou, Takashi; Mercer, Julian F. B.; Akiyama, Shin-ichi; Furukawa, Tatsuhiko

doi:10.1158/0008-5472.can-06-3096

Cited by 54 publications

(59 citation statements)

References 22 publications

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“…These genes are unlikely to be involved in [5] Increased in cisplatin efflux mediated by copper transporter. Paclitaxel resistance unexplained, no efflux or presence of P-gp A2780 Ovarian ↑Aurora-A Transfection Resistant Resistant [58] Aurora-A induces survival by activating Akt growth signalling C33A Cervical ↑BAG-1 Transfection Resistant Resistant [59] Increased expression of anti-apoptotic BAG-1 ↓Apoptosis A2780 Ovarian ↑Bcl-Xl Transfection Resistant Resistant [60] Increased expression of anti-apoptotic Bcl-Xl ↓Apoptosis HeLa Cervical ↓COX-2 siRNA Resistant Resistant [61] ↓Apoptosis in response to both cisplatin and paclitaxel [62] ↓Apoptosis in response to both cisplatin and paclitaxel…”

Section: Cisplatin/paclitaxel Cross Resistance or Cross Sensitivitymentioning

confidence: 99%

“…The overexpression of ATP7A by transfection produced cross resistance between cisplatin and paclitaxel which was unexpected [5] . Low-level resistance to cisplatin was mediated by ATP7As role as an efflux protein for platinum [84] .…”

Section: Skov3mentioning

confidence: 99%

“…These studies will often amplify or reduce the expression of a gene to a greater extent to what would be observed in the development of drug resistance in cancer patients but nevertheless provide insight into which pathways can mediate resistance. Transfection studies have linked the overexpression of copper efflux transporters ATP7A [5] and ATP7B [6] with cisplatin resistance. Decreasing the expression of DNA repair gene ERCC1 by siRNA [7] or glutathione transferase GSTP1 [8] by antisense has been shown to mediate sensitivity to cisplatin.…”

Section: Introductionmentioning

confidence: 99%

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A Systematic Review of Genes Involved in the Inverse Resistance Relationship Between Cisplatin and Paclitaxel Chemotherapy: Role of BRCA1

Stordal¹,

Davey

2009

CCDT

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A systematic review of cell models of acquired drug resistance not involving genetic manipulation showed that 80% of cell models had an inverse resistance relationship between cisplatin and paclitaxel [1] . Here we systematically review genetically modified cell lines in which the inverse cisplatin/paclitaxel resistance phenotype has resulted. This will form a short list of genes which may play a role in the mechanism of the inverse resistance relationship as well as potential markers for monitoring the development of resistance in the clinical treatment of cancer. The literature search revealed 91 genetically modified cell lines which report toxicity or viability/apoptosis data for cisplatin and paclitaxel relative to their parental cell lines. This resulted in 26 genes being associated with the inverse cisplatin/paclitaxel phenotype. The gene with the highest number of genetically modified cell lines associated with the inverse resistance relationship was BRCA1 and this gene is discussed in detail with reference to chemotherapy response in cell lines and in the clinical treatment of breast, ovarian and lung cancer. Other genes associated with the inverse resistance phenotype included dihydrodiol dehydrogenase (DDH) and P-glycoprotein. Genes which caused cross resistance or cross sensitivity between cisplatin and paclitaxel were also examined, the majority of these genes were apoptosis associated genes which may be useful for predicting cross resistance. We propose that BRCA1 should be the first of a panel of cellular markers to predict the inverse cisplatin/paclitaxel resistance phenotype.3

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Section: Cisplatin/paclitaxel Cross Resistance or Cross Sensitivitymentioning

confidence: 99%

Section: Skov3mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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A Systematic Review of Genes Involved in the Inverse Resistance Relationship Between Cisplatin and Paclitaxel Chemotherapy: Role of BRCA1

Stordal¹,

Davey

2009

CCDT

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“…Overexpression of ATP7A was reported previously to render cells resistant to several classes of chemotherapeutic drugs in addition to the platinum-containing agents (Owatari et al, 2007;Furukawa et al, 2008). To determine whether loss of Sec61␤ modulated sensitivity to other classes of drugs in human ovarian cancer, parental cells and 2008 Sec61␤-KD cells were exposed to increasing concentrations of etoposide, vincristine, doxorubicin, and paclitaxel, each of which belongs to a different mechanistic class.…”

Section: Downloaded Frommentioning

confidence: 99%

“…In addition to being associated with resistance to platinum-containing drugs, ATP7A has been shown to confer resistance to other chemotherapeutic agents. It is more difficult to explain how ATP7A might mediate resistance to less structurally related compounds, and some investigators hypothesized that, in addition to serving as a copper export pump, ATP7A regulates an overall vesicle secretory process that is involved in the efflux of many compounds (Owatari et al, 2007;Furukawa et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

Sec61β Controls Sensitivity to Platinum-Containing Chemotherapeutic Agents through Modulation of the Copper-Transporting ATPase ATP7A

Abada¹,

Larson

Manorek

et al. 2012

Mol Pharmacol

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The Sec61 protein translocon is a multimeric complex that transports proteins across lipid bilayers. We discovered that the Sec61␤ subunit modulates cellular sensitivity to chemotherapeutic agents, particularly the platinum drugs. To investigate the mechanism, expression of Sec61␤ was constitutively knocked down in 2008 ovarian cancer cells. Sec61␤ knockdown (KD) resulted in 8-, 16.8-, and 9-fold resistance to cisplatin (cDDP), carboplatin, and oxaliplatin, respectively. Sec61␤ KD reduced the cellular accumulation of cDDP to 67% of that in parental cells. Baseline copper levels, copper uptake, and copper cytotoxicity were also reduced. Because copper transporters and chaperones regulate platinum drug accumulation and efflux, their expression in 2008 Sec61␤-KD cells was analyzed; ATP7A was found to be 2-to 3-fold overexpressed, whereas there was no change in ATP7B, ATOX1, CTR1, or CTR2 levels. Cells lacking ATP7A did not exhibit increased cDDP resistance upon knockdown of Sec61␤. Sec61␤-KD cells also exhibited altered ATP7A cellular distribution. We conclude that Sec61␤ modulates the cytotoxicity of many chemotherapeutic agents, with the largest effect being on the platinum drugs. This modulation occurs through effects of Sec61␤ on the expression and distribution of ATP7A, which was shown previously to control platinum drug sequestration and cytotoxicity.

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Annexin A4-conferred platinum resistance is mediated by the copper transporter ATP7A

et al. 2013

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Although platinum drugs are often used for the chemotherapy of human cancers, platinum resistance is a major issue and may preclude their use in some cases. We recently reported that enhanced expression of Annexin A4 (Anx A4) increases chemoresistance to carboplatin through increased extracellular efflux of the drug. However, the precise mechanisms underlying that chemoresistance and the relationship of Anx A4 to platinum resistance in vivo remain unclear. In this report, the in vitro mechanism of platinum resistance induced by Anx A4 was investigated in endometrial carcinoma cells (HEC1 cells) with low expression of Anx A4. Forced expression of Anx A4 in HEC1 cells resulted in chemoresistance to platinum drugs. In addition, HEC1 control cells were compared with Anx A4‐overexpressing HEC1 cells in xenografted mice. Significantly greater chemoresistance to cisplatin was observed in vivo in Anx A4‐overexpressing xenografted mice. Immunofluorescence analysis revealed that exposure to platinum drugs induced relocation of Anx A4 from the cytoplasm to the cellular membrane, where it became colocalized with ATP7A, a copper transporter also well known as a mechanism of platinum efflux. ATP7A expression suppressed by small interfering RNA had no effect on HEC1 control cells in terms of chemosensitivity to platinum drugs. However, suppression of ATP7A in Anx A4‐overexpressing platinum‐resistant cells improved chemosensitivity to platinum drugs (but not to 5‐fluorouracil) to a level comparable to that of control cells. These results indicate that enhanced expression of Anx A4 confers platinum resistance by promoting efflux of platinum drugs via ATP7A.

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Copper-Transporting P-Type ATPase, ATP7A, Confers Multidrug Resistance and Its Expression Is Related to Resistance to SN-38 in Clinical Colon Cancer

Cited by 54 publications

References 22 publications

A Systematic Review of Genes Involved in the Inverse Resistance Relationship Between Cisplatin and Paclitaxel Chemotherapy: Role of BRCA1

A Systematic Review of Genes Involved in the Inverse Resistance Relationship Between Cisplatin and Paclitaxel Chemotherapy: Role of BRCA1

Sec61β Controls Sensitivity to Platinum-Containing Chemotherapeutic Agents through Modulation of the Copper-Transporting ATPase ATP7A

Annexin A4-conferred platinum resistance is mediated by the copper transporter ATP7A

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