Thapsigargin resistance in human prostate cancer cells

Authors

  • John P. O'Neill BS,

    1. Greenebaum Cancer Center, University of Maryland School of Medicine, Baltimore, Maryland
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    • The first 2 authors contributed equally to this work.

  • Chidambaram Natesa Velalar PhD,

    1. Greenebaum Cancer Center, University of Maryland School of Medicine, Baltimore, Maryland
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    • The first 2 authors contributed equally to this work.

  • Dong Ik Lee PhD,

    1. Greenebaum Cancer Center, University of Maryland School of Medicine, Baltimore, Maryland
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  • Bin Zhang MD, PhD,

    1. Greenebaum Cancer Center, University of Maryland School of Medicine, Baltimore, Maryland
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  • Takeo Nakanishi PhD,

    1. Greenebaum Cancer Center, University of Maryland School of Medicine, Baltimore, Maryland
    2. Division of Medical Oncology, University of Maryland School of Medicine, Baltimore, Maryland
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  • Yao Tang MD,

    1. Greenebaum Cancer Center, University of Maryland School of Medicine, Baltimore, Maryland
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  • Florin Selaru MD,

    1. Greenebaum Cancer Center, University of Maryland School of Medicine, Baltimore, Maryland
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  • Douglas Ross MD, PhD,

    1. Greenebaum Cancer Center, University of Maryland School of Medicine, Baltimore, Maryland
    2. Division of Medical Oncology, University of Maryland School of Medicine, Baltimore, Maryland
    3. Baltimore Veterans Affairs Medical Center, Baltimore, Maryland
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  • Stephen J. Meltzer MD,

    1. Greenebaum Cancer Center, University of Maryland School of Medicine, Baltimore, Maryland
    2. Division of Gastroenterology, University of Maryland School of Medicine, Baltimore, Maryland
    3. Baltimore Veterans Affairs Medical Center, Baltimore, Maryland
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  • Arif Hussain MD

    Corresponding author
    1. Greenebaum Cancer Center, University of Maryland School of Medicine, Baltimore, Maryland
    2. Division of Medical Oncology, University of Maryland School of Medicine, Baltimore, Maryland
    3. Baltimore Veterans Affairs Medical Center, Baltimore, Maryland
    • Division of Hematology and Oncology, University of Maryland Cancer Center, BRB RM: 9-041, 655 W. Baltimore St., Baltimore, MD 21201
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    • Fax: (410) 328-0805


Abstract

BACKGROUND.

Thapsigargin (TG) is a potent inhibitor of sarcoplasmic/endoplasmic reticulum Ca2+ ATPases (SERCAs). TG-based prodrugs are being developed for the treatment of prostate cancer (PC). To develop optimal TG-based therapeutics it is important to understand the mechanisms of resistance to TG that may potentially occur in cancer cells.

METHODS.

DU145/TG and PC3/TG cells were derived from human PC DU145 and PC3 cells, respectively, by incremental exposure to TG. Growth assays, Western blot analyses, cDNA microarrays, semiquantitative and real-time polymerase chain reaction (PCR), Northern blot analyses, and immunohistochemistry were used to study these cells.

RESULTS.

DU145/TG cells are 1100-fold and PC3/TG cells are 1350-fold resistant to TG. Although expression of both SERCA and p-glycoprotein can mediate TG resistance in hamster cells, neither is modulated in DU145/TG cells. In contrast, in PC3/TG cells, SERCA, and not p-glycoprotein, is significantly overexpressed but cannot by itself account for the 1350-fold resistance to TG in these cells. Several genes not previously identified to be altered by TG selection are modulated in DU145/TG and PC3/TG cells. Furthermore, the spectrum of genes modulated in DU145/TG cells are distinct from that in PC3/TG cells, even though both cells are of prostate origin and share the same TG-resistant phenotype.

CONCLUSIONS.

PC cells can adapt to SERCA inhibition by TG. However, they demonstrate cell type-specific plasticity with respect to gene expression upon TG selection. Further, previously not described mechanisms of resistance appear to be recruited in the TG-resistant PC cells, which provide a novel model to study mechanisms of resistance and adaptation in PC on TG-mediated dysregulation of Ca2+ homeostasis. Cancer 2006. © 2006 American Cancer Society.

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