Abstract 4510: SHH and GATA interplay: A potential therapeutic target for prostate cancer

Abstract

Abstract Background: Prostate cancer is the second leading cause of cancer deaths in males worldwide. Typically, prostate cancer cells depend on androgens, and many therapeutic strategies target receptors involved in androgen regulation. However, certain castration-resistant tumors of the prostate are resistant to androgen deprivation therapies. Moreover, advanced-stage prostate tumors can proliferate uncontrollably either due to androgens or due to alteration in other signaling pathways. For instance, the activity of the sonic hedgehog (SHH) pathway, which usually decreases during post-natal development, is increased during prostate cancer progression. Of interest, a recent study reported a novel role for GATA transcription factors as potential repressors of SHH signaling. Based on the above-mentioned findings, we hypothesize that the balance between GATA and SHH pathways is perturbed in prostate cancer leading to overactivation of SHH pathways and its downstream effector proteins. Methods: We screened human prostate cancer cell lines, DU145, 22Rv1, and PC3, as well as a human immortalized normal prostate epithelial cell line, RWPE-1, for baseline levels of expression of SHH downstream effector proteins via real-time PCR using specific primers. Subsequently, we treated the cell lines with bone morphogenetic protein 4 (BMP4)-conditioned media in order to induce the expression of GATA transcription factors, and then we measured the levels of expression for each of the SHH pathway effector proteins by real-time PCR. Results: We demonstrated that GATA can interfere with the expression of SHH and its effector proteins in the human prostate cancer cell lines. Upon treatment with BMP4, we noted that there was a decrease in expression of Gli1, Gli2, and Gli3, downstream effectors of SHH, suggesting an anti-proliferative response. Additionally, Patched1 expression was also attenuated after treatment with BMP4. Similarly, Sox9 expression was also abrogated. Conclusion: Our results demonstrate that GATA transcription factors can act as potential repressors of the SHH pathway in the context of prostate cancer in vitro by interfering with the expression of SHH downstream effector proteins. Citation Format: Rami Z. Morsi, Wassim Abou Kheir, Layal El-Khatib, Hiba Msheik, Georges Daoud. SHH and GATA interplay: A potential therapeutic target for prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4510.