gant-61 and Neoplasm-Metastasis

Due to its importance in the pathogenesis of oral squamous cell carcinoma (OSCC), the Hedgehog (HH) pathway is considered a potential therapeutic target. We investigated the effects of GANT61, a GLI inhibitor, on HH gene expression, as well as on metastatic OSCC cell proliferation and death. Following culture in DMEM medium, cytotoxicity of GANT61 against different tumor and non-tumor cell types was assessed by alamarBlue assays. Cytotoxicity analysis revealed that the metastatic HSC3 cell line was the most sensitive (IC

Topics: Adult; Apoptosis; Carcinoma, Squamous Cell; Cell Proliferation; Cell Survival; Cells, Cultured; Gene Expression Regulation, Neoplastic; Humans; Mouth Neoplasms; Neoplasm Metastasis; Pyridines; Pyrimidines; Zinc Finger Protein GLI1

Dysregulation of hedgehog pathway is observed in numerous cancers. Relevance of hedgehog pathway genes in cancer cohort and inhibition of its downstream effector (GLI1) towards metastasis in cell lines are explored in the study.. One hundred fifty fresh tumours of breast cancer patients were collected for the study. Based on differential expression, panel of 6 key regulators of the pathway (SHH, DHH, IHH, PTCH1, SMO and GLI1) in microarray datasets were identified. Expressional profiles of aforementioned genes were later correlated with clinico-pathological parameters in Pakistani breast cancer cohort at transcript and protein levels. In addition, GLI1 over expressing breast cancer cell lines (MDA-MB-231 and MCF-7) were treated with GANT61 to explore its probable effects on metastasis.. SHH, DHH, PTCH1 and GLI1 were significantly over-expressed in tumours as compared with respective normal mammary tissues. A significant correlation of SHH, DHH and GLI1 expression with advanced tumour size, stages, grades, nodal involvement and distant metastasis was observed (p < 0.05). Over-expression of SHH, DHH and GLI1 was significantly related with patients having early onset and pre-menopausal status. Of note, hedgehog pathway was frequently up regulated in luminal B and triple negative breast cancer affected women. In addition, positive correlations were observed among aforementioned members of pathway and Ki67 (r-value: 0.63-0.78) emphasizing their role towards disease progression. Exposure of GANT61 (inhibitor for GLI1) significantly restricted cell proliferation, reduced cell motility and invasion.. Role of activated hedgehog pathway in breast cancer metastasis provides a novel target for cancer therapy against aggressive cancer subtypes.

Topics: Apoptosis; Breast Neoplasms; Cell Line, Tumor; Cell Movement; Cell Proliferation; Female; Hedgehog Proteins; Humans; MCF-7 Cells; Neoplasm Grading; Neoplasm Metastasis; Neoplasm Staging; Patched-1 Receptor; Proportional Hazards Models; Pyridines; Pyrimidines; Signal Transduction; Zinc Finger Protein GLI1

Recent fate-mapping studies concluded that EMT is not required for metastasis of carcinomas. Here we challenge this conclusion by showing that these studies failed to account for possible crosstalk between EMT and non-EMT cells that promotes dissemination of non-EMT cells. In breast cancer models, EMT cells induce increased metastasis of weakly metastatic, non-EMT tumour cells in a paracrine manner, in part by non-cell autonomous activation of the GLI transcription factor. Treatment with GANT61, a GLI1/2 inhibitor, but not with IPI 926, a Smoothened inhibitor, blocks this effect and inhibits growth in PDX models. In human breast tumours, the EMT-transcription factors strongly correlate with activated Hedgehog/GLI signalling but not with the Hh ligands. Our findings indicate that EMT contributes to metastasis via non-cell autonomous effects that activate the Hh pathway. Although all Hh inhibitors may act against tumours with canonical Hh/GLI signalling, only GLI inhibitors would act against non-canonical EMT-induced GLI activation.

Topics: Animals; Breast Neoplasms; Cell Line, Tumor; Epithelial-Mesenchymal Transition; Female; Heterografts; Humans; Mice, Inbred NOD; Mice, SCID; Neoplasm Metastasis; Paracrine Communication; Pyridines; Pyrimidines; Tumor Microenvironment; Veratrum Alkaloids; Zinc Finger Protein GLI1

The HH signaling pathway is a 'core' signal transduction pathway in pancreatic cancer that promotes the tumorigenesis of pancreatic cancers via enhancing cell proliferation, increasing invasion and metastasis and protecting against apoptosis. In the present study, we found that HH signaling regulates autophagy in pancreatic cancer cells. Activation of HH signaling inhibits autophagy, while inhibition of the HH pathway induces autophagy. Although the role of autophagy in cell survival and apoptosis may depend on tumor type and the microenvironment, our data clearly demonstrated that GANT61-induced autophagy contributed to reduced viability and increased apoptosis in pancreatic cancer cells both in vivo and in vitro, and these effects were reversed by the autophagy inhibitor, 3-MA. We propose that HH signaling by regulating autophagy plays an important role in determining the cellular response to HH-targeted therapy in pancreatic cancer and further investigation of the interaction between autophagy and HH signaling is particularly important.

Topics: Adenocarcinoma; Animals; Apoptosis; Autophagy; Carcinoma, Pancreatic Ductal; Cell Line, Tumor; Cell Proliferation; Cell Survival; Cell Transformation, Neoplastic; Female; Hedgehog Proteins; Humans; Kruppel-Like Transcription Factors; Mice; Mice, Inbred BALB C; Mice, Nude; Neoplasm Invasiveness; Neoplasm Metastasis; Nuclear Proteins; Pancreatic Ducts; Pancreatic Neoplasms; Pyridines; Pyrimidines; Signal Transduction; Transcription Factors; Xenograft Model Antitumor Assays; Zinc Finger Protein GLI1; Zinc Finger Protein Gli2