An old friend with new skills: Imiquimod as novel inhibitor of Hedgehog signaling in basal cell carcinoma.

Wolfgang Gruber,Anna-Maria Frischauf,Fritz Aberger

doi:10.18632/oncoscience.80

Wolfgang Gruber, Anna-Maria Frischauf + Show 1 more

Open Access

https://doi.org/10.18632/oncoscience.80

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Journal: Oncoscience	Publication Date: Sep 16, 2014
Citations: 89	License type: cc-by

Affiliation: University of Salzburg

Abstract

Deregulated Hedgehog (HH)/GLI signaling plays an etiologic role in the initiation, progression and maintenance of many cancers. Small molecule targeting of HH signaling by inhibiting the essential pathway effector Smoothened (SMO) has proven exceptionally efficient for the treatment of advanced and metastatic basal cell carcinoma. That said, severe side effects, limited response rates, SMO-independent GLI signaling and rapid development of drug resistance limit the therapeutic success of SMO antagonists, urgently calling for the identification of alternative and additional strategies repressing oncogenic HH signaling. In this perspective article we highlight recent findings showing that the Toll-like receptor-7/8 (TLR7/8) agonist imiquimod (IMQ), an immune modulator approved for the treatment of basal cell carcinoma, can also act as a potent cell autonomous inhibitor of oncogenic HH signaling. Surprisingly, IMQ reduces HH signal strength independent of TLR signaling, via adenosine receptor (ADORA)/Adenylate cyclase (AC)/Protein kinase A (PKA) activation. We here highlight the molecular mechanisms of IMQ-mediated repression of HH/GLI and discuss the possible benefits as well as challenges of using ADORA agonists for the treatment of HH-associated cancer.

Highlights

HH/GLI signaling is crucial for proper embryonic development and in adults for tissue maintenance and regeneration by regulating stem cell activation and self-renewal
basal cell carcinomas (BCC) cells do not express detectable levels of the cognate IMQ receptors Toll-like receptor-7/8 (TLR7/8), neither did genetic inhibition of the essential TLR effector MYD88 affect the repressive activity of IMQ on HH/GLI signaling
A study analyzing hematopoietic progenitors in flies has identified adenosine/ADORA signaling as a negative regulator of Hh signaling via activation of protein kinase A (PKA) and repression of the fly GLI homologue Cubitus interruptus [77]. In line with these data, we observed that treatment of BCC cells or human GLI expressing keratinocytes with IMQ induced PKA-mediated GLI phosphorylation, thereby reducing the level of GLI activator and oncogenic HH signal strength, respectively (Figure 1)

Summary

Introduction

HH/GLI signaling is crucial for proper embryonic development and in adults for tissue maintenance and regeneration by regulating stem cell activation and self-renewal. In the study by Wolff et al [75], we tested for a putative direct effect of IMQ on HH signaling and found that IMQ directly blocks HH pathway activation in cultured murine BCC cells as evidenced by the repression of HH target genes including Gli[1].

Results

Conclusion