Direct estradiol and diethylstilbestrol actions on early- versus late-stage prostate cancer cells

Luke Y. Koong, Cheryl S. Watson

    Research output: Contribution to journalArticle

    11 Citations (Scopus)

    Abstract

    BACKGROUND: Diethylstilbestrol (DES) and other pharmaceutical estrogens have been used at ≥ µM concentrations to treat advanced prostate tumors, with successes primarily attributed to indirect hypothalamic-pituitary-testicular axis control mechanisms. However, estrogens also directly affect tumor cells, though the mechanisms involved are not well understood.

    METHODS: LAPC-4 (androgen-dependent) and PC-3 (androgen-independent) cell viability was measured after estradiol (E2) or DES treatment across wide concentration ranges. We then examined multiple rapid signaling mechanisms at 0.1 nM E2 and 1 µM DES optima including levels of: activation (phosphorylation) for mitogen-activated protein kinases, cell-cycle proteins, and caspase 3, necroptosis, and reactive oxygen species (ROS).

    RESULTS: LAPC-4 cells were more responsive than PC-3 cells. Robust and sustained extracellular-regulated kinase activation with E2 , but not DES, correlated with ROS generation and cell death. c-Jun N-terminal kinase was only activated in E2-treated PC-3 cells and was not correlated with caspase 3-mediated apoptosis; necroptosis was not involved. The cell-cycle inhibitor protein p16(INK4A) was phosphorylated in both cell lines by both E2 and DES, but to differing extents. In both cell types, both estrogens activated p38 kinase, which subsequently phosphorylated cyclin D1, tagging it for degradation, except in DES-treated PC-3 cells.

    CONCLUSIONS: Cyclin D1 status correlated most closely with disrupted cell cycling as a cause of reduced cell numbers, though other mechanisms also contributed. As low as 0.1 nM E2 effectively elicited these mechanisms, and its use could dramatically improve outcomes for both early- and late-stage prostate cancer patients, while avoiding the side effects of high-dose DES treatment.

    Original languageEnglish (US)
    Pages (from-to)1589-1603
    Number of pages15
    JournalThe Prostate
    Volume74
    Issue number16
    DOIs
    StatePublished - Dec 1 2014

    Fingerprint

    Diethylstilbestrol
    Estradiol
    Prostatic Neoplasms
    Cell Cycle Proteins
    Estrogens
    Cyclin D1
    Caspase 3
    Androgens
    Reactive Oxygen Species
    Phosphotransferases
    Cyclin-Dependent Kinase Inhibitor p16
    JNK Mitogen-Activated Protein Kinases
    Mitogen-Activated Protein Kinases
    Prostate
    Neoplasms
    Cell Survival
    Cell Death
    Cell Count
    Phosphorylation
    Apoptosis

    Keywords

    • apoptosis
    • cell cycle
    • estrogen receptors
    • MAP kinases
    • non-genomic
    • reactive oxygen species

    ASJC Scopus subject areas

    • Medicine(all)

    Cite this

    Direct estradiol and diethylstilbestrol actions on early- versus late-stage prostate cancer cells. / Koong, Luke Y.; Watson, Cheryl S.

    In: The Prostate, Vol. 74, No. 16, 01.12.2014, p. 1589-1603.

    Research output: Contribution to journalArticle

    Koong, Luke Y. ; Watson, Cheryl S. / Direct estradiol and diethylstilbestrol actions on early- versus late-stage prostate cancer cells. In: The Prostate. 2014 ; Vol. 74, No. 16. pp. 1589-1603.
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    N2 - BACKGROUND: Diethylstilbestrol (DES) and other pharmaceutical estrogens have been used at ≥ µM concentrations to treat advanced prostate tumors, with successes primarily attributed to indirect hypothalamic-pituitary-testicular axis control mechanisms. However, estrogens also directly affect tumor cells, though the mechanisms involved are not well understood.METHODS: LAPC-4 (androgen-dependent) and PC-3 (androgen-independent) cell viability was measured after estradiol (E2) or DES treatment across wide concentration ranges. We then examined multiple rapid signaling mechanisms at 0.1 nM E2 and 1 µM DES optima including levels of: activation (phosphorylation) for mitogen-activated protein kinases, cell-cycle proteins, and caspase 3, necroptosis, and reactive oxygen species (ROS).RESULTS: LAPC-4 cells were more responsive than PC-3 cells. Robust and sustained extracellular-regulated kinase activation with E2 , but not DES, correlated with ROS generation and cell death. c-Jun N-terminal kinase was only activated in E2-treated PC-3 cells and was not correlated with caspase 3-mediated apoptosis; necroptosis was not involved. The cell-cycle inhibitor protein p16(INK4A) was phosphorylated in both cell lines by both E2 and DES, but to differing extents. In both cell types, both estrogens activated p38 kinase, which subsequently phosphorylated cyclin D1, tagging it for degradation, except in DES-treated PC-3 cells.CONCLUSIONS: Cyclin D1 status correlated most closely with disrupted cell cycling as a cause of reduced cell numbers, though other mechanisms also contributed. As low as 0.1 nM E2 effectively elicited these mechanisms, and its use could dramatically improve outcomes for both early- and late-stage prostate cancer patients, while avoiding the side effects of high-dose DES treatment.

    AB - BACKGROUND: Diethylstilbestrol (DES) and other pharmaceutical estrogens have been used at ≥ µM concentrations to treat advanced prostate tumors, with successes primarily attributed to indirect hypothalamic-pituitary-testicular axis control mechanisms. However, estrogens also directly affect tumor cells, though the mechanisms involved are not well understood.METHODS: LAPC-4 (androgen-dependent) and PC-3 (androgen-independent) cell viability was measured after estradiol (E2) or DES treatment across wide concentration ranges. We then examined multiple rapid signaling mechanisms at 0.1 nM E2 and 1 µM DES optima including levels of: activation (phosphorylation) for mitogen-activated protein kinases, cell-cycle proteins, and caspase 3, necroptosis, and reactive oxygen species (ROS).RESULTS: LAPC-4 cells were more responsive than PC-3 cells. Robust and sustained extracellular-regulated kinase activation with E2 , but not DES, correlated with ROS generation and cell death. c-Jun N-terminal kinase was only activated in E2-treated PC-3 cells and was not correlated with caspase 3-mediated apoptosis; necroptosis was not involved. The cell-cycle inhibitor protein p16(INK4A) was phosphorylated in both cell lines by both E2 and DES, but to differing extents. In both cell types, both estrogens activated p38 kinase, which subsequently phosphorylated cyclin D1, tagging it for degradation, except in DES-treated PC-3 cells.CONCLUSIONS: Cyclin D1 status correlated most closely with disrupted cell cycling as a cause of reduced cell numbers, though other mechanisms also contributed. As low as 0.1 nM E2 effectively elicited these mechanisms, and its use could dramatically improve outcomes for both early- and late-stage prostate cancer patients, while avoiding the side effects of high-dose DES treatment.

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    KW - reactive oxygen species

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