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Molecular Pharmacology

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Research ArticleArticle

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

Paolo B. Abada, Christopher A. Larson, Gerald Manorek, Preston Adams and Stephen B. Howell
Molecular Pharmacology September 2012, 82 (3) 510-520; DOI: https://doi.org/10.1124/mol.112.079822
Paolo B. Abada
Moores Cancer Center (P.B.A., C.A.L., G.M., P.A., S.B.H.) and Department of Medicine (S.B.H.), University of California, San Diego, La Jolla, California
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Christopher A. Larson
Moores Cancer Center (P.B.A., C.A.L., G.M., P.A., S.B.H.) and Department of Medicine (S.B.H.), University of California, San Diego, La Jolla, California
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Gerald Manorek
Moores Cancer Center (P.B.A., C.A.L., G.M., P.A., S.B.H.) and Department of Medicine (S.B.H.), University of California, San Diego, La Jolla, California
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Preston Adams
Moores Cancer Center (P.B.A., C.A.L., G.M., P.A., S.B.H.) and Department of Medicine (S.B.H.), University of California, San Diego, La Jolla, California
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Stephen B. Howell
Moores Cancer Center (P.B.A., C.A.L., G.M., P.A., S.B.H.) and Department of Medicine (S.B.H.), University of California, San Diego, La Jolla, California
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Abstract

The Sec61 protein translocon is a multimeric complex that transports proteins across lipid bilayers. We discovered that the Sec61β subunit modulates cellular sensitivity to chemotherapeutic agents, particularly the platinum drugs. To investigate the mechanism, expression of Sec61β was constitutively knocked down in 2008 ovarian cancer cells. Sec61β knockdown (KD) resulted in 8-, 16.8-, and 9-fold resistance to cisplatin (cDDP), carboplatin, and oxaliplatin, respectively. Sec61β 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 Sec61β-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 Sec61β. Sec61β-KD cells also exhibited altered ATP7A cellular distribution. We conclude that Sec61β modulates the cytotoxicity of many chemotherapeutic agents, with the largest effect being on the platinum drugs. This modulation occurs through effects of Sec61β on the expression and distribution of ATP7A, which was shown previously to control platinum drug sequestration and cytotoxicity.

Footnotes

  • ↵Embedded Image The online version of this article (available at http://molpharm.aspetjournals.org) contains supplemental material.

  • This work was supported by grants from the National Institutes of Health National Cancer Institute [Grants T32-CA121938, CA152185, CA095298]; and a grant from the Tower Cancer Research Foundation.

  • Article, publication date, and citation information can be found at http://molpharm.aspetjournals.org.

    http://dx.doi.org/10.1124/mol.112.079822.

  • ABBREVIATIONS:

    ARF
    ADP-ribosylation factor
    GEF
    guanine nucleotide exchange factor
    BCS
    bathocuproine disulfonate
    cDDP
    cisplatin
    ICP
    inductively coupled plasma
    MS
    mass spectrometry
    KD
    knockdown
    PBS
    phosphate-buffered saline
    ER
    endoplasmic reticulum
    MES
    4-morpholineethanesulfonic acid
    qRT-PCR
    quantitative reverse transcription-polymerase chain reaction
    shRNA
    short hairpin RNA.

  • Received May 8, 2012.
  • Accepted June 18, 2012.
  • Copyright © 2012 The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 82 (3)
Molecular Pharmacology
Vol. 82, Issue 3
1 Sep 2012
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Research ArticleArticle

Sec61β Control of Platinum Drug Sensitivity

Paolo B. Abada, Christopher A. Larson, Gerald Manorek, Preston Adams and Stephen B. Howell
Molecular Pharmacology September 1, 2012, 82 (3) 510-520; DOI: https://doi.org/10.1124/mol.112.079822

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Research ArticleArticle

Sec61β Control of Platinum Drug Sensitivity

Paolo B. Abada, Christopher A. Larson, Gerald Manorek, Preston Adams and Stephen B. Howell
Molecular Pharmacology September 1, 2012, 82 (3) 510-520; DOI: https://doi.org/10.1124/mol.112.079822
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