The Hedgehog (Hh) pathway is activated in some human cancers, including medulloblastoma. The gliomaassociated oncogene homolog (GLI) transcription factors are critical mediators of the activated Hh pathway, and their expression may be elevated in some tumors independent of upstream Hh signaling. Thus, therapies targeting GLI transcription factors may benefit a wide spectrum of patients with mutations at different nodal points of the Hh pathway. In this study, we present evidence that arsenic trioxide (ATO) suppresses human cancer cell growth and tumor development in mice by inhibiting GLI1. Mechanistically, ATO directly bound to GLI1 protein, inhibited its transcriptional activity, and decreased expression of endogenous GLI target genes. Consistent with this, ATO inhibited the growth of human cancer cell lines that depended on upregulated GLI expression in vitro and in vivo in

The target of rapamycin (TOR) pathway is highly conserved among eukaryotes and has evolved to couple nutrient sensing to cellular growth. TOR is found in two distinct signaling complexes in cells, TOR complex 1 (TORC1) and TOR complex 2 (TORC2). These complexes are differentially regulated and act as effectors for the generation of signals that drive diverse cellular processes such as growth, proliferation, protein synthesis, rearrangement of the cytoskeleton, autophagy, metabolism and survival. Mammalian TOR (mTOR) is very important for development in embryos, while in adult organisms it is linked to aging and lifespan effects. In humans, the mTOR pathway is implicated in the tumorigenesis of multiple cancer types and its deregulation is associated with familial cancer syndromes. Because of its high biological relevance, different therapeutic strategies have been developed to target this signaling cascade, resulting in the emergence of unique pharmacological inhibitors that are either already approved for use in clinical oncology or currently under preclinical or clinical development. Multimodal treatment strategies that simultaneously target multiple nodes of the pathway and/or negative feedback regulatory loops may ultimately provide the best therapeutic advantage in targeting this pathway for the treatment of malignancies.

Ewing sarcoma family of tumors (ESFT) is an undifferentiated neoplasm of the bone and soft tissue. ESFT is characterized by a specific chromosomal translocation occurring between chromosome 22 and (in most cases) chromosome 11, which generates an aberrant transcription factor, EWS-FLI1. The function of EWS-FLI1 is essential for the maintenance of ESFT cell survival and tumorigenesis. The Hedgehog pathway is activated in several cancers. Oncogenic potential of the Hedgehog pathway is mediated by increasing the activity of the GLI family of transcription factors. Recent evidence suggests that EWS-FLI1 increases expression of GLI1 by an unknown mechanism. Our data from chromatin immunoprecipitation and promoter reporter studies indicated GLI1 as a direct transcriptional target of EWS-FLI1. Expression of EWS-FLI1 in non-ESFT cells increased GLI1 expression and GLI-dependent transcription. We also detected high levels of GLI1 protein in ESFT cell lines. Pharmacological inhibition of GLI1 protein function decreased proliferation and soft agar colony formation of ESFT cells. Our results establish GLI1 as a direct transcriptional target of EWS-FLI1 and suggest a potential role for GLI1 in ESFT tumorigenesis. Ewing Sarcoma Family of Tumors (ESFT)2 affects patients between the ages of 3 and 40 with most cases occurring during the second decade of life. It is an undifferentiated small round cell tumor of the bone and soft tissue with an unknown cell of origin. Currently, the cure rate for patients with localized disease is only 70%, and is less than 30% for patients showing metastatic disease despite intensive multimodal treatment strategies (1). There is a need for more effective therapies to treat ESFT, especially in patients with metastases. ESFT is characterized by chromosomal translocations occurring between the genes for the TET (TAF15, EWS, and TLS) family member protein EWS and members of the ETS family of DNA-binding transcription factors. In ϳ90% of the cases, the translocation occurs between chromosome 22 and chromosome 11 (2). This results in expression of a fusion protein EWS-FLI1, which acts as an aberrant transcription factor whose persistent expression is necessary to maintain the viability of ESFT cells (3-5). The ability of EWS-FLI1 to alter transcription of several target genes such as PTPL1, ID2, and TGF␤-RII is very important to its function in tumor formation and progression (6 -9).The Hedgehog (Hh) pathway is activated in several cancers such as basal cell carcinoma, medulloblastoma, rhabdomyosarcoma, and cancers of the pancreas, lung, colon, stomach, and prostate (10 -18). The pathway is composed of three Hh ligands (Sonic, Indian, and Desert Hh) that all bind to the Patched1 receptor. In the absence of Hh ligand, Patched inhibits another transmembrane protein, Smoothened. When Patched is engaged by the Hh ligand, Smoothened is activated because of diminished inhibitory signal from Patched. The signal is then transduced to the important downstream effectors GLI1, GLI2, and GLI3, which act as transcr...

SUMMARY We provide evidence that the Unc-51-like kinase 1 (ULK1) is activated during engagement of the Type I IFN receptor (IFNR). Our studies demonstrate that the function of ULK1 is required for gene transcription mediated via IFN-stimulated response elements (ISRE) and IFNγ activation site (GAS) elements and controls expression of key IFN-stimulated genes (ISGs). We identify ULK1 as an upstream regulator of p38α MAPK and establish that the regulatory effects of ULK1 on ISG expression are mediated possibly by engagement of the p38 MAPK pathway. Importantly, we demonstrate that ULK1 is essential for antiproliferative responses and Type I IFN-induced antineoplastic effects against malignant erythroid precursors from patients with myeloproliferative neoplasms. Together, these data reveal a role for ULK1 as a key mediator of Type I IFNR-generated signals that control gene transcription and induction of antineoplastic responses.