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

Luke Y. Koong, Cheryl S. Watson

Research output: Contribution to journalArticlepeer-review

20 Scopus citations


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 p16INK4A 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
Issue number16
StatePublished - Dec 1 2014
Externally publishedYes


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

ASJC Scopus subject areas

  • Oncology
  • Urology


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