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Research ArticleCellular and Molecular

The Autophagy-Senescence Connection in Chemotherapy: Must Tumor Cells (Self) Eat Before They Sleep?

Rachel W. Goehe, Xu Di, Khushboo Sharma, Molly L. Bristol, Scott C. Henderson, Kristoffer Valerie, Francis Rodier, Albert R. Davalos and David A. Gewirtz
Journal of Pharmacology and Experimental Therapeutics December 2012, 343 (3) 763-778; DOI: https://doi.org/10.1124/jpet.112.197590
Rachel W. Goehe
Departments of Pharmacology and Toxicology (R.W.G., K.S., D.A.G.), Radiation Oncology (R.W.G., K.V.), Pathology (M.L.B.), and Anatomy and Neurobiology (S.C.H.), Virginia Commonwealth University, Richmond, Virginia; Center of Drug Evaluation and Research, Food and Drug Administration, Silver Spring, Maryland (X.D.); Département de Radiologie, Université de Montréal, Montreal, Canada (F.R.); Centre Hospitalier de l'Université de Montréal et Institut du Cancer de Montréal, Montreal, Canada (F.R.); and Lawrence Berkeley National Laboratory, Berkeley, California (A.R.D.)
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Xu Di
Departments of Pharmacology and Toxicology (R.W.G., K.S., D.A.G.), Radiation Oncology (R.W.G., K.V.), Pathology (M.L.B.), and Anatomy and Neurobiology (S.C.H.), Virginia Commonwealth University, Richmond, Virginia; Center of Drug Evaluation and Research, Food and Drug Administration, Silver Spring, Maryland (X.D.); Département de Radiologie, Université de Montréal, Montreal, Canada (F.R.); Centre Hospitalier de l'Université de Montréal et Institut du Cancer de Montréal, Montreal, Canada (F.R.); and Lawrence Berkeley National Laboratory, Berkeley, California (A.R.D.)
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Khushboo Sharma
Departments of Pharmacology and Toxicology (R.W.G., K.S., D.A.G.), Radiation Oncology (R.W.G., K.V.), Pathology (M.L.B.), and Anatomy and Neurobiology (S.C.H.), Virginia Commonwealth University, Richmond, Virginia; Center of Drug Evaluation and Research, Food and Drug Administration, Silver Spring, Maryland (X.D.); Département de Radiologie, Université de Montréal, Montreal, Canada (F.R.); Centre Hospitalier de l'Université de Montréal et Institut du Cancer de Montréal, Montreal, Canada (F.R.); and Lawrence Berkeley National Laboratory, Berkeley, California (A.R.D.)
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Molly L. Bristol
Departments of Pharmacology and Toxicology (R.W.G., K.S., D.A.G.), Radiation Oncology (R.W.G., K.V.), Pathology (M.L.B.), and Anatomy and Neurobiology (S.C.H.), Virginia Commonwealth University, Richmond, Virginia; Center of Drug Evaluation and Research, Food and Drug Administration, Silver Spring, Maryland (X.D.); Département de Radiologie, Université de Montréal, Montreal, Canada (F.R.); Centre Hospitalier de l'Université de Montréal et Institut du Cancer de Montréal, Montreal, Canada (F.R.); and Lawrence Berkeley National Laboratory, Berkeley, California (A.R.D.)
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Scott C. Henderson
Departments of Pharmacology and Toxicology (R.W.G., K.S., D.A.G.), Radiation Oncology (R.W.G., K.V.), Pathology (M.L.B.), and Anatomy and Neurobiology (S.C.H.), Virginia Commonwealth University, Richmond, Virginia; Center of Drug Evaluation and Research, Food and Drug Administration, Silver Spring, Maryland (X.D.); Département de Radiologie, Université de Montréal, Montreal, Canada (F.R.); Centre Hospitalier de l'Université de Montréal et Institut du Cancer de Montréal, Montreal, Canada (F.R.); and Lawrence Berkeley National Laboratory, Berkeley, California (A.R.D.)
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Kristoffer Valerie
Departments of Pharmacology and Toxicology (R.W.G., K.S., D.A.G.), Radiation Oncology (R.W.G., K.V.), Pathology (M.L.B.), and Anatomy and Neurobiology (S.C.H.), Virginia Commonwealth University, Richmond, Virginia; Center of Drug Evaluation and Research, Food and Drug Administration, Silver Spring, Maryland (X.D.); Département de Radiologie, Université de Montréal, Montreal, Canada (F.R.); Centre Hospitalier de l'Université de Montréal et Institut du Cancer de Montréal, Montreal, Canada (F.R.); and Lawrence Berkeley National Laboratory, Berkeley, California (A.R.D.)
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Francis Rodier
Departments of Pharmacology and Toxicology (R.W.G., K.S., D.A.G.), Radiation Oncology (R.W.G., K.V.), Pathology (M.L.B.), and Anatomy and Neurobiology (S.C.H.), Virginia Commonwealth University, Richmond, Virginia; Center of Drug Evaluation and Research, Food and Drug Administration, Silver Spring, Maryland (X.D.); Département de Radiologie, Université de Montréal, Montreal, Canada (F.R.); Centre Hospitalier de l'Université de Montréal et Institut du Cancer de Montréal, Montreal, Canada (F.R.); and Lawrence Berkeley National Laboratory, Berkeley, California (A.R.D.)
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Albert R. Davalos
Departments of Pharmacology and Toxicology (R.W.G., K.S., D.A.G.), Radiation Oncology (R.W.G., K.V.), Pathology (M.L.B.), and Anatomy and Neurobiology (S.C.H.), Virginia Commonwealth University, Richmond, Virginia; Center of Drug Evaluation and Research, Food and Drug Administration, Silver Spring, Maryland (X.D.); Département de Radiologie, Université de Montréal, Montreal, Canada (F.R.); Centre Hospitalier de l'Université de Montréal et Institut du Cancer de Montréal, Montreal, Canada (F.R.); and Lawrence Berkeley National Laboratory, Berkeley, California (A.R.D.)
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David A. Gewirtz
Departments of Pharmacology and Toxicology (R.W.G., K.S., D.A.G.), Radiation Oncology (R.W.G., K.V.), Pathology (M.L.B.), and Anatomy and Neurobiology (S.C.H.), Virginia Commonwealth University, Richmond, Virginia; Center of Drug Evaluation and Research, Food and Drug Administration, Silver Spring, Maryland (X.D.); Département de Radiologie, Université de Montréal, Montreal, Canada (F.R.); Centre Hospitalier de l'Université de Montréal et Institut du Cancer de Montréal, Montreal, Canada (F.R.); and Lawrence Berkeley National Laboratory, Berkeley, California (A.R.D.)
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Abstract

Exposure of MCF-7 breast tumor cells or HCT-116 colon carcinoma cells to clinically relevant concentrations of doxorubicin (Adriamycin; Farmitalia Research Laboratories, Milan, Italy) or camptothecin results in both autophagy and senescence. To determine whether autophagy is required for chemotherapy-induced senescence, reactive oxygen generation induced by Adriamycin was suppressed by N-acetyl cysteine and glutathione, and the induction of ataxia telangiectasia mutated, p53, and p21 was modulated pharmacologically and/or genetically. In all cases, autophagy and senescence were collaterally suppressed. The close association between autophagy and senescence indicated by these experiments reflects their collateral regulation via common signaling pathways. The potential relationship between autophagy and senescence was further examined through pharmacologic inhibition of autophagy with chloroquine and 3-methyl-adenine and genetic ablation of the autophagy-related genes ATG5 and ATG7. However, inhibition of autophagy by pharmacological and genetic approaches could not entirely abrogate the senescence response, which was only reduced and/or delayed. Taken together, our findings suggest that autophagy and senescence tend to occur in parallel, and furthermore that autophagy accelerates the development of the senescent phenotype. However, these responses are not inexorably linked or interdependent, as senescence can occur when autophagy is abrogated.

Footnotes

  • R.W.G. and X.D. contributed equally to this work.

  • The Virginia Commonwealth University Flow Cytometry and Imaging Shared Resource Facility is supported in part by the National Institutes of Health National Cancer Institute [Grant P30CA16059]. R.W.G. was supported by the National Institutes of Health National Cancer Institute [Grant T32 CA113277-04]. KV was supported in part by the National Institutes of Health [Grants R01-NS064593, R21-CA156995].

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

    http://dx.doi.org/10.1124/jpet.112.197590.

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

  • ABBREVIATIONS:

    SA-β-gal
    senescence-associated β-galactosidase
    ADR
    Adriamycin
    AOS
    acridine orange staining
    ATM
    ataxia telangiectasia mutated
    AVO
    acidic vesicular organelle
    CPT
    camptothecin
    CQ
    chloroquine
    DCF
    2′,7′-dichlorofluorescin
    FACS
    fluorescence-activated cell sorting
    GSH
    glutathione
    KU-55933
    2-morpholin-4-yl-6-thianthren-1-yl-pyran-4-one
    3-MA
    3-methyl-adenine
    NAC
    N-acetyl cysteine
    PBS
    phosphate-buffered saline
    pRb
    retinoblastoma protein
    Rb
    retinoblastoma
    ROS
    reactive oxygen species
    shControl
    shRNA against a scramble control
    shRNA
    short-haired RNA
    shATM
    shRNA against ATM
    shp21
    shRNA against p21
    shATG
    shRNA against ATG.

  • Received July 13, 2012.
  • Accepted August 24, 2012.
  • Copyright © 2012 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 343 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 343, Issue 3
1 Dec 2012
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Research ArticleCellular and Molecular

Adriamycin-Induced Senescence and Autophagy

Rachel W. Goehe, Xu Di, Khushboo Sharma, Molly L. Bristol, Scott C. Henderson, Kristoffer Valerie, Francis Rodier, Albert R. Davalos and David A. Gewirtz
Journal of Pharmacology and Experimental Therapeutics December 1, 2012, 343 (3) 763-778; DOI: https://doi.org/10.1124/jpet.112.197590

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Research ArticleCellular and Molecular

Adriamycin-Induced Senescence and Autophagy

Rachel W. Goehe, Xu Di, Khushboo Sharma, Molly L. Bristol, Scott C. Henderson, Kristoffer Valerie, Francis Rodier, Albert R. Davalos and David A. Gewirtz
Journal of Pharmacology and Experimental Therapeutics December 1, 2012, 343 (3) 763-778; DOI: https://doi.org/10.1124/jpet.112.197590
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