Androgenic Regulation Of Hedgehog Signaling Pathway Components In Prostate Cancer Cells

Main Category: Prostate / Prostate Cancer
Also Included In: Urology / Nephrology;  Cancer / Oncology
Article Date: 05 Apr 2009 - 0:00 PDT

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UroToday.com - Tumors share many characteristics with developing embryonic tissues including the presence of rapidly dividing cells and cells in multiple states of differentiation. Therefore, it should not be surprising that the cellular signaling processes that govern normal embryonic development play some role in tumor biology. Hedgehog (Hh) is one of the fundamental developmental signaling pathways that is believed to have a role in prostate cancer. Hh signaling is driven by a family of ligands, referred to as "hedgehogs", that bind to a cell surface receptor protein, Patched, activating a signaling cascade that upregulates gene transcription mediated by Gli transcription factors. For prostate cancer, reports that hedgehog ligands and Gli are overexpressed in the tumor cells supports the idea that these tumor cells might have abnormally activated autocrine Hedgehog signaling. Likewise, experimental evidence that the Hh signaling inhibitor, cyclopamine, or Gli knockdown suppresses prostate cancer cell growth provides pre-clinical evidence to support the use of Hh inhibitors for prostate cancer. However, a recent study from Dr. Wade Bushman's group at the University of Wisconsin1 failed to find any evidence for autocrine hedgehog signaling in the most commonly utilized human prostate cancer cell lines and this report raises important questions regarding the nature of the molecular pathway through which Hh signaling components become dysregulated in prostate cancer.

Our experimental work, described in this publication, shows that androgen regulates the expression of key components of the Hh signaling pathway, at least in the androgen-sensitive human prostate cancer LNCaP cells and in other derivatives of this cell line. When grown in the presence of androgen, these cells express very little, if any, hedgehog ligand. Yet, when they are switched to an androgen-depleted growth medium, they become virtual "hedgehog factories", upregulating Sonic, Indian and Desert hedgehog mRNA and protein expression up to 30,000-fold. The burst of hedgehog production was accompanied by the awakening of autocrine hedgehog signaling in the tumor cells as measured by upregulation of endogenous GLI target genes. Moreover, the induced hedgehog ligands were secreted out into the medium of androgen-deprived cells and we showed that they are paracrine-active and able to drive Hh signaling in mouse bone pre-osteoblasts, an activity that is associated with osteoblastic differentiation of these cells. Finally, in contrast to hedgehog ligands that were upregulated by androgen deprivation, GLI1 expression was upregulated by androgen in LNCaP cells. We attribute this novel activity to the potential consequence of the ETS gene fusion in these cells since GLI is known to be a target of the EWS:ETS fusion gene in Ewing Sarcoma cells2. In summary, our experimental work showed that some of the most important components of the Hh signaling pathway are regulated by androgen action in this model prostate cancer cell system. Whereas, the published work was restricted to the use of LNCaP cell derivatives, we have also observed these same results using androgen-sensitive VCaP cells. Moreover, the clinical relevance of our findings is supported by a recent report from a group of French investigators that describes upregulated hedgehog ligand expression in prostate tumors from hormone-treated patients3.

Based upon the cumulative evidence, we believe that the data support consideration of the use of anti-Hh therapy as an adjuvant for hormone therapy in the treatment of advanced or castration-resistant prostate cancer. For these tumors, Hh signaling blockade might supplement hormone therapy by further slowing the proliferative rate of tumor cells as well as by suppressing their potential for further metastatic spread or bone-related co-morbidity. Whereas the common anti-hedgehog agent, cyclopamine, is a difficult drug to work with due to its extreme hydrophobicity, there are other anti-Hh therapeutics currently in development and we would encourage clinical trials to assess effectiveness of these new agents along with hormone therapy.

References
1 Zhang J, Lipinski R, Shaw A, Gipp J, Bushman W. J Urol, 177: 1179-85, 2007.
2 Zwerner JP, Joo J, Warner KL, Christensen L, et al. Oncogene, 22: 3282-91, 2008.
3 Azouly S, Terry S, Chimingqi M, Sirah N, et al. J Pathol, 216: 460-70, 2008.

Written by Ralph Buttyan, PhD, et al. as part of Beyond the Abstract on UroToday.com

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