Histone deacetylase (HDAC)-inhibitors (HDACis) are well characterized anti-cancer agents with promising results in clinical trials. However, mechanistically little is known regarding their selectivity in killing malignant cells while sparing normal cells. Gene expression-based chemical genomics identified HDACis as being particularly potent against Down syndrome associated myeloid leukemia (DS-AMKL) blasts. Investigating the anti-leukemic function of HDACis revealed their transcriptional and posttranslational regulation of key autophagic proteins, including ATG7. This leads to suppression of autophagy, a lysosomal degradation process that can protect cells against damaged or unnecessary organelles and protein aggregates. DS-AMKL cells exhibit low baseline autophagy due to mTOR activation. Consequently, HDAC inhibition repressed autophagy below a critical threshold, which resulted in accumulation of mitochondria, production of reactive oxygen species, DNA-damage and apoptosis. Those HDACi-mediated effects could be reverted upon autophagy activation or aggravated upon further pharmacological or genetic inhibition. Our findings were further extended to other major acute myeloid leukemia subgroups with low basal level autophagy. The constitutive suppression of autophagy due to mTOR activation represents an inherent difference between cancer and normal cells. Thus, via autophagy suppression, HDACis deprive cells of an essential pro-survival mechanism, which translates into an attractive strategy to specifically target cancer cells.
MicroRNAs (miRNAs) play a pivotal role in the regulation of hematopoiesis and development of leukemia. Great interest emerged in modulating miRNA expression for therapeutic purposes. In order to identify miRNAs, which specifically suppress leukemic growth of acute myeloid leukemia (AML) with t(8;21), inv(16) or mixed lineage leukemia (MLL) rearrangement by inducing differentiation, we conducted a miRNA expression profiling in a cohort of 90 cytogenetically characterized, de novo pediatric AML cases. Four miRNAs, specifically downregulated in MLL-rearranged, t(8;21) or inv(16) AMLs, were characterized by their tumor-suppressive properties in cell lines representing those respective cytogenetic groups. Among those, forced expression of miR-9 reduced leukemic growth and induced monocytic differentiation of t(8;21) AML cell lines in vitro and in vivo. The tumor-suppressive functions of miR-9 were specifically restricted to AML cell lines and primary leukemic blasts with t(8;21). On the other hand, these functions were not evident in AML blasts from patients with MLL rearrangements. We showed that miR-9 exerts its effects through the cooperation with let-7 to repress the oncogenic LIN28B/HMGA2 axis. Thus, miR-9 is a tumor suppressor-miR which acts in a stringent cell context-dependent manner.
The Hedgehog signaling pathway plays a pivotal role during embryonic development, stem cell maintenance, and wound healing. Hedgehog signaling also is deregulated in many cancers. However, the role of this signaling pathway in the carcinogenesis of cholangiocarcinoma (CCC) is still unknown. In this study, we investigated the effects of Hedgehog inhibition by cyclopamine and 5E1 in cultured human CCC cell lines and in vivo using a xenograft mouse model. We also investigated the involvement of Hedgehog in epithelial to mesenchymal transition (EMT), migration, and CCC tumor growth. Sonic hedgehog (Shh) ligand was highly expressed in 89% of human CCC tissues and in CCC cell lines. Cyclopamine and 5E1 treatments effectively inhibited cell proliferation, migration, and invasion by down-regulating the Hedgehog target genes glioblastoma 1 and glioblastoma 2. In vitro and in vivo, we detected an increase in epithelial marker, E-cadherin, after Hedgehog inhibition. In addition, we saw an increase in necrotic areas and a decrease in mitotic figures in cyclopamine and 5E1-treated CCC xenograft tumors. Conclusion: This study supports the presence of autocrine Hedgehog signaling in human CCC, where CCC cells produce and respond to Shh ligand. Blocking the Hedgehog pathway inhibited EMT and decreased the viability of CCC cells. In addition, cyclopamine and 5E1 inhibited the growth of CCC xenograft tumors. (HEPATOLOGY 2013;57:1035-1045 T he incidence and mortality rate of cholangiocarcinoma (CCC) is increasing worldwide.
Cholangiocacinoma (CC) is a cancer disease with rising incidence. Notch signaling has been shown to be deregulated in many cancers. However, the role of this signaling pathway in the carcinogenesis of CC is still not fully explored. In this study, we investigated the effects of Notch inhibition by γ-secretase inhibitor IX (GSI IX) in cultured human CC cell lines and we established a transgenic mouse model with liver specific expression of the intracellular domain of Notch (Notch-ICD) and inactivation of tumor suppressor p53. GSI IX treatment effectively impaired cell proliferation, migration, invasion, epithelial to mesenchymal transition and growth of softagar colonies. In vivo overexpression of Notch-ICD together with an inactivation of p53 significantly increased tumor burden and showed CC characteristics. Conclusion: Our study highlights the importance of Notch signaling in the tumorigenesis of CC and demonstrates that additional inactivation of p53 in vivo.
Pancreatic ductal adenocarcinoma (PDAC) is an aggressive disease with a high rate of metastasis. Recent studies have indicated that Notch and janus kinase 2 (JAK2)/signal transducers and activators of transcription 3 (STAT3) signaling pathways are both important for the initiation and progression of PDAC. The purpose of this study was to determine the outcome of targeting these two tumor signaling pathways simultaneously both in vitro and in vivo. We assessed the combinational effects of the γ-secretase inhibitor IX (GSI IX) and JAK2 inhibitor (AG-490) on growth and epithelial plasticity of human pancreatic cancer cell lines, and in a genetically engineered mouse model (Pdx1-Cre, LSL-KrasG12D, p53(lox/+)) of PDAC. Dual treatment with GSI IX and AG-490 significantly impaired cell proliferation, migration, invasion, soft agar growth and apoptosis when compared with monotherapies. Most importantly, combinational treatment significantly attenuates tumor progression in vivo and suppresses conversion from acinar-ductal-metaplasia to PDAC. Our results suggest that targeting Notch and JAK2/STAT3 signaling pathways simultaneously is superior to single inhibitions, supporting combined treatment by GSI IX and AG-490 as a potential therapeutic approach for PDAC. However, the study design limits the direct transfer into the clinic and the impact of dual treatment in patients with PDAC remains still to be determined.
Pancreatic ductal adenocarcinoma (PDAC) is an aggressive disease with a high rate of metastasis. Recent studies have indicated that the Notch signalling pathway is important in PDAC initiation and maintenance, although the specific cell biological roles of the pathway remain to be established. Here we sought to examine this question in established pancreatic cancer cell lines using the γ-secretase inhibitor IX (GSI IX) to inactivate Notch. Based on the known roles of Notch in development and stem cell biology, we focused on effects on epithelial mesenchymal transition (EMT) and on pancreatic tumor initiating CD44+/EpCAM+ cells. We analyzed the effect of the GSI IX on growth and epithelial plasticity of human pancreatic cancer cell lines, and on the tumorigenicity of pancreatic tumor initiating CD44+/EpCAM+ cells. Notably, apoptosis was induced after GSI IX treatment and EMT markers were selectively targeted. Furthermore, under GSI IX treatment, decline in the growth of pancreatic tumor initiating CD44+/EpCAM+ cells was observed in vitro and in a xenograft mouse model. This study demonstrates a central role of Notch signalling pathway in pancreatic cancer pathogenesis and identifies an effective approach to inhibit selectively EMT and suppress tumorigenesis by eliminating pancreatic tumor initiating CD44+/EpCAM+ cells.
Capsaicin, the most abundant pungent molecule produced by pepper plants, represents an important ingredient in spicy foods consumed throughout the world. Studies have shown that capsaicin can relieve inflammation and has anti-proliferative effects on various human malignancies. Cholangiocarcinoma (CC) is a cancer disease with rising incidence. The prognosis remains dismal with little advance in treatment. The aim of the present study is to explore the anti-tumor activity of capsaicin in cultured human CC cell lines. Capsaicin effectively impaired cell proliferation, migration, invasion, epithelial to mesenchymal transition and growth of softagar colonies. Further, we show that capsaicin treatment of CC cells regulates the Hedgehog signaling pathway. Conclusion: Our results provide a basis for capsaicin to improve the prognosis of CCs in vivo and present new insights into the effectiveness and mode of action of capsaicin.
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