Abstract 3900: STAT3 inhibition with Galiellalactone effectively targets the prostate cancer stem-like cell population

Abstract

Abstract Introduction and objectives Cancer stem-like cells (CSCs) represent a small subpopulation of largely quiescent cells that reside within tumors. Several studies have demonstrated that this small population is more resistant to current therapies and is therefore directly responsible for tumor recurrence. The transcription factor STAT3 has been recently related to the regulation of the stem cell niche in prostate cancer (PCa), and inhibition of activated STAT3 (pSTAT3) seems to be a valid strategy to selectively target PCa CSCs. We have previously shown that pSTAT3 blockade by Galielallactone (GL) not only reduces proliferation and induces apoptosis of prostate cancer cells in vitro, but also inhibits the growth of prostate tumors and the metastatic spread to regional and distal lymph nodes in vivo. Here we performed experiments aimed at studying the effect of the inhibitor GL on PCa CSCs, in order to increase our understanding on this compound as a promising therapeutic approach for prostate cancer patients. Materials and methods The expression of stem, basal and luminal cell surface markers (CD133/CD44/CD24) was analyzed by FACS on DU145 and PC3 cells treated with GL. DU145 cells were sorted based on expression of the above markers and then plated for further analysis, including expression of pSTAT3 by IHC and cell proliferation by the WST1 assay. The effect of GL on clonogenic recovery of PCa CSCs was studied by colony formation with sorted cells. Results Our results show that the CSC populations (CD133+/CD44+) express high levels of activated pSTAT3 compared to the CD44+/CD24+ cell population. Treatment with GL decreased the number of CSCs in DU145 cells after 48h, whilst the number of CD44+/CD24+ cells was less affected. Importantly, treatment with GL had no effect on CD133+/CD44+ or CD44+/CD24+ populations in PC3 cells, which don’t express pSTAT3. Of note, both CD133+/CD44+ and CD44+/CD24+ cells responded to treatment with GL, as proliferation decreased in a dose-dependent manner. Treatment with GL significantly reduced the ability of CSCs to form colonies in a concentration-dependent manner. Conclusion This study demonstrates that the STAT3 inhibitor Galiellalactone can specifically target the prostate cancer stem-like cell population in vitro, implying that pSTAT3 inhibition by GL could represent a valid therapeutic strategy to antagonize CSCs in human prostate cancer. Future experiments will be aimed at validating these data and relating the clonogenic inhibition to the effects of pSTAT3 blockade by GL on tumor initiation by prostate cancer stem-like cells in vivo. Citation Format: Giacomo Canesin, Anne T. Collins, Rebecka Hellsten, Norman J. Maitland, Anders Bjartell. STAT3 inhibition with Galiellalactone effectively targets the prostate cancer stem-like cell population [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3900. doi:10.1158/1538-7445.AM2017-3900