All-trans-retinoic acid antagonizes the hedgehog pathway by inducing patched

Abstract

Male germ cell tumors (GCTs) are a model for a curable solid tumor. GCTs can differentiate into mature teratomas. Embryonal carcinomas (ECs) represent the stem cell compartment of GCTs and are the malignant counterpart to embryonic stem (ES) cells. GCTs and EC cells are useful to investigate differentiation therapy and chemotherapy response. This study explored mechanistic interactions between all-trans-retinoic acid (RA), which induces differentiation of EC and ES cells, and the Hedgehog (Hh) pathway, a regulator of self-renewal and proliferation. RA was found to induce mRNA and protein expression of Patched 1 (Ptch1), the Hh ligand receptor and negative regulator of this pathway. PTCH1 is also a target gene of Hh signaling through Smoothened (Smo) activation. Yet, this observed RA-mediated Ptch1 induction was independent of Smo. It occurred despite co-treatment with RA and Smo inhibitors. Retinoid induction of Ptch1 also occurred in other RA-responsive cancer cell lines and in normal ES cells. Notably, this enhanced Ptch1 expression was preceded by induction of the homeobox transcription factor Meis1, a direct RA target. Direct interaction between Meis1 and Ptch1 was confirmed using chromatin immunoprecipitation assays. To establish the translational relevance of this work, Ptch1 expression was shown to be deregulated in human ECs relative to mature teratoma and the normal seminiferous tubule. Taken together, these findings reveal a previously unrecognized mechanism through which RA can inhibit the Hh pathway via Ptch1 induction. Engaging this pathway is a new way to repress the Hh pathway that can be translated into the cancer clinic.

Low dose isotretinoin as an adjuvant therapy for treatment of different clinical variants of warts: A case series

“…Benign HPV serotypes, not only high‐risk HPV, are implicated in Hh signal transduction. Oral retinoids was found to induce mRNA and protein expression of Patched 1, the Hh ligand receptor and negative regulator of this pathway (Busch et al, ).…”

“…protein expression of Patched 1, the Hh ligand receptor and negative regulator of this pathway(Busch et al, 2014).Oral retinoids have shown an impressive therapeutic response in comparison and in addition to conventional therapies used for warts, with significant clinical response, extended remission time, and infrequent relapses. In a recent randomized trial to compare the efficacy of topical versus oral isotretinoin in the treatment of plane warts, 69% of patients in the low dose oral isotretinoin group (0.5 mg/kg/d) had complete remission, whereas 38% of patients in the topical isotretinoin group showed complete response(Kaur, Brar, Kumar, Brar, & Singh, 2017).…”

ALDH1A1 Deficiency in Gorlin Syndrome Suggests a Central Role for Retinoic Acid and ATM Deficits in Radiation Carcinogenesis

“…The Hedgehog pathway is the primary focal point in Gorlin syndrome and experimental evidence highlights a significant intertwined relationship between the retinoic acid and Hedgehog pathways. Specifically, retinoic acid can antagonize the Hedgehog pathway by inducing Patched [ 30 ] and there are a number of reports demonstrating that the retinoic acid and Hedgehog pathways interact in developmental biology [ 31 ]. Retinoic acid deficiency, therefore, has the potential to eliminate a negative feedback process for the Hedgehog pathway.…”

“…Due to severe adverse side-effects retinoic acid is not used to manage cancer in Gorlin syndrome patients and alternative retinoid pharmacons (e.g., Tazarotene) with significantly reduced toxicity show promise as alternative therapeutics [ 8 ]. Among the pleiotropic effects of retinoids, the regulation of stem cell differentiation has led to important applications in differentiation therapy [ 30 ]. It is noteworthy that short term (24 h) retinoic acid treatment in vitro can induce human stem cell differentiation [ 45 ].…”

Arsenic Trioxide, Itraconazole, All-Trans Retinoic Acid and Nicotinamide: A Proof of Concept for Combined Treatments with Hedgehog Inhibitors in Advanced Basal Cell Carcinoma

“…They can heterodimerize and recognize specific retinoic acid response elements (RAREs) in genes promoter regions. It has been reported that RA-treatment increases PTCH1 expression, through homeobox transcription factor Myeloid Ecotropic Viral Integration Site [40], with consequent inhibition of SMO and repression of the Hh signaling pathway. Its target genes include GLI1, PTCH1, CCND1, and cyclin E. RA-mediated induction of PTCH1 did not depend on SMO since their inhibitors do not prevent the induction [40].…”