Abstract
Abstract Background: Prostate cancer is the second leading cause of death and the most commonly diagnosed cancer in males in the US. Very limited therapeutic modalities are available for treatment of androgen refractory advanced stage prostate carcinomas. Therefore, understanding the molecular basis of the disease and development of newer strategies for prevention and treatment of prostate cancer is urgently needed. An important signaling pathway that is known to operate in most types of cancer, including prostate cancer, is the aberrant β-catenin signaling. Inappropriate β-catenin/Wnt signaling leads to the accumulation of β-catenin in the nucleus where it functions as a co-transcription factor to transcribe proto-oncogenes. In addition, β-catenin has also been shown to cross-talk and modulate the transcription activity of other factors including estrogen and androgen receptors. Therefore, strategies to regulate this specific signaling pathway using synthetic or natural agents can be developed as a novel therapeutic modality for the treatment of prostate cancer. Ormeloxifene is a synthetic, non-steroidal triphenyl ethylene compound that has been widely used as an oral contraceptive and has demonstrated promising results in the inhibition of breast cancer. Herein, we have investigated the effect of ormeloxifene on prostate cancer cell growth and its effect on β-catenin transcription activity. Methods: The effect of ormeloxifene on cell proliferation, anchorage dependent colony formation, anchorage independent growth, cell motility, and invasion of prostate cancer cells were determined using standard techniques. β-catenin/T cell factor (TCF) transcription activity was measured by luciferase reporter assays using reporter constructs Topflash or Fopflash and pRL-TK (Renilla luciferase). Luciferase activities were assayed using Dual Glo reagent. The expression and subcellular localization of proteins was determined by immunoblotting and confocal microscopy. Results: Ormeloxifene demonstrated inhibition of cell proliferation in all the four (LNCaP, C4-2, PC3 and DU145) prostate cell lines in a dose dependent manner. In addition, ormeloxifene also effectively suppressed clonogenic, cell motility and invasive characteristics of C4-2 androgen-refractory prostate cancer cells. Repression of these cellular phenotypes was correlated with attenuation of β-catenin/TCF4 trasncriptional activity. The inhibition of the β-catenin/TCF4 signaling was also reflected in the decreased expression of c-Myc, a downstream target of the β-catenin/TCF4 signaling pathway upon ormeloxifene treatment. Conclusion: Our findings suggest that ormeloxifene effectively inhibits tumorigenic characteristics of prostate cancer cells via intervention/attenuation of β-catenin/TCF4 signaling pathway. It may therefore be a novel therapeutic modality for the treatment and management of prostate cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3806. doi:1538-7445.AM2012-3806
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