scholarly journals Inhibition of the sonic hedgehog pathway activates TGF-β-activated kinase (TAK1) to induce autophagy and suppress apoptosis in thyroid tumor cells

2021 ◽  
Vol 12 (5) ◽  
Author(s):  
Sumei Li ◽  
Jingxiang Wang ◽  
Yurong Lu ◽  
Yuqing Zhao ◽  
Richard A. Prinz ◽  
...  
Keyword(s):  
Tumor Growth ◽  
Sonic Hedgehog ◽  
Anaplastic Thyroid Cancer ◽  
Thyroid Tumor ◽  
Shh Pathway ◽  
Compound C ◽  
Mechanistic Investigation ◽  
Pathway Inhibition ◽  
Induced Apoptosis ◽  
Thyroid Cancer Cell Lines

AbstractThe sonic hedgehog (Shh) pathway is highly activated in a variety of malignancies and plays important roles in tumorigenesis, tumor growth, drug resistance, and metastasis. Our recent study showed that the inhibitors of the Shh pathway such as cyclopamine (CP), a Smothened (SMO) inhibitor, and GANT61, a Gli1 inhibitor, have modest inhibitory effects on thyroid tumor cell proliferation and tumor growth. The objective of this study was to determine whether autophagy was induced by inhibition of the Shh pathway and could negatively regulate GANT61-induced apoptosis. Here we report that inhibition of the Shh pathway by Gli1 siRNA or by cyclopamine and GANT61 induced autophagy in SW1736 and KAT-18 cells, two anaplastic thyroid cancer cell lines; whereas Gli1 overexpression suppressed autophagy. Mechanistic investigation revealed that inhibition of the Shh pathway activated TAK1 and its two downstream kinases, the c-Jun-terminal kinase (JNK) and AMP-activated protein kinase (AMPK). GANT61-induced autophagy was blocked by TAK1 siRNA and the inhibitors of TAK1 (5Z-7-oxozeaenol, 5Z), JNK (SP600125), and AMPK (Compound C, CC). Inhibition of autophagy by chloroquine and 5Z and by TAK1 and Beclin-1 siRNA enhanced GANT61-induced apoptosis and its antiproliferative activity. Our study has shown that inhibition of the Shh pathway induces autophagy by activating TAK1, whereas autophagy in turn suppresses GANT61-induced apoptosis. We have uncovered a previously unrecognized role of TAK1 in Shh pathway inhibition-induced autophagy and apoptosis.

scholarly journals Targeting the Sonic Hedgehog Pathway to Suppress the Expression of the Cancer Stem Cell (CSC)—Related Transcription Factors and CSC-Driven Thyroid Tumor Growth

Cancers ◽  
2021 ◽  
Vol 13 (3) ◽  
pp. 418
Author(s):  
Yurong Lu ◽  
Yiwen Zhu ◽  
Shihan Deng ◽  
Yuhuang Chen ◽  
Wei Li ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Stem Cell ◽  
Transcription Factors ◽  
Thyroid Cancer ◽  
Tumor Growth ◽  
Sonic Hedgehog ◽  
Thyroid Tumor ◽  
Self Renewal ◽  
Sox2 Expression ◽  
Shh Pathway

The sonic hedgehog (Shh) pathway plays important roles in tumorigenesis, tumor growth, drug resistance, and metastasis. We and others have reported earlier that this pathway is highly activated in thyroid cancer. However, its role in thyroid cancer stem cell (CSC) self-renewal and tumor development remains incompletely understood. B lymphoma Mo-MLV insertion region 1 homolog (BMI1) and SRY-Box Transcription Factor 2 (SOX2) are two CSC-related transcription factors that have been implicated in promoting CSC self-renewal. The objective of our current investigation was to determine the role of the Shh pathway in regulating BMI1 and SOX2 expression in thyroid cancer and promoting thyroid tumor growth and development. Here we report that inhibition of the Shh pathway by Gli1 siRNA or by cyclopamine and GANT61 reduced BMI1 and SOX2 expression in SW1736 and KAT-18 cells, two anaplastic thyroid cancer cell lines. The opposite results were obtained in cells overexpressing Gli1 or its downstream transcription factor Snail. The Shh pathway regulated SOX2 and BMI1 expression at a transcriptional and post-transcriptional level, respectively. GANT61 treatment suppressed the growth of SW1736 CSC-derived tumor xenografts but did not significantly inhibit the growth of tumors grown from bulk tumor cells. Clinicopathological analyses of thyroid tumor specimens by immunohistochemical (IHC) staining revealed that BMI1 and SOX2 were highly expressed in thyroid cancer and correlated with Gli1 expression. Our study provides evidence that activation of the Shh pathway leads to increased BMI1 and SOX2 expression in thyroid cancer and promotes thyroid CSC-driven tumor initiation. Targeting the Shh pathway may have therapeutic value for treating thyroid cancer and preventing recurrence.

scholarly journals Overactivated sonic hedgehog signaling aggravates intrauterine adhesion via inhibiting autophagy in endometrial stromal cells

2020 ◽  
Vol 11 (9) ◽  
Author(s):  
Cheng Wei ◽  
Yibin Pan ◽  
Yinli Zhang ◽  
Yongdong Dai ◽  
Lingling Jiang ◽  
...  
Keyword(s):  
Wound Healing ◽  
Sonic Hedgehog ◽  
Hedgehog Signaling ◽  
Sonic Hedgehog Signaling ◽  
Endometrial Stromal Cells ◽  
Shh Pathway ◽  
Intrauterine Adhesion ◽  
Stromal Cell Line ◽  
Pathway Inhibition ◽  
The Impact

Abstract Autophagy can be dynamically induced in response to stresses and is an essential, ubiquitous intracellular recycling system that impacts the fate of damaged resident cells, thereby influencing wound healing. Endometrial fibrosis is a form of abnormal wound healing that causes intrauterine adhesion (IUA) and infertility. We previously demonstrated that overactivated sonic hedgehog (SHH) signaling exacerbated endometrial fibrosis, but the role of autophagy in this process is still unknown. Here, we report that impaired autophagy participates in SHH pathway-induced endometrial fibrosis. Endometrial stroma-myofibroblast transition accompanied by autophagy dysfunction was present in both endometrial biopsies of IUA patients and Amhr2cre/+R26-SmoM2+/− (AM2) transgenic mouse. Mechanistically, SHH pathway negatively regulated autophagy through pAKT-mTORC1 in a human endometrial stromal cell line (T-HESCs). Furthermore, SHH pathway-mediated fibrosis was partly counteracted by autophagy modulation in both T-HESCs and the murine IUA model. Specifically, the impact of SHH pathway inhibition (GANT61) was reversed by the pharmacological autophagy inhibitor chloroquine (CQ) or RNA interference of autophagy-related gene ATG5 or ATG7. Similar results were obtained from the murine IUA model treated with GANT61 and CQ. Moreover, promoting autophagy with rapamycin reduced fibrosis in the AM2 IUA model to baseline levels. In summary, defective autophagy is involved in SHH pathway-driven endometrial fibrosis, suggesting a potential novel molecular target for IUA treatment.

scholarly journals Activation of the Sonic Hedgehog pathway in thyroid neoplasms and its potential role in tumor cell proliferation

2012 ◽  
Vol 19 (2) ◽  
pp. 167-179 ◽  
Author(s):  
Xiulong Xu ◽  
Helen Ding ◽  
Geetha Rao ◽  
Shalini Arora ◽  
Constantine P Saclarides ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Thyroid Cancer ◽  
Tumor Cell ◽  
Sonic Hedgehog ◽  
Thyroid Neoplasms ◽  
Thyroid Tumor ◽  
Tumor Cell Proliferation ◽  
Thyroid Carcinomas ◽  
Shh Pathway ◽  
Genes Encoding

The sonic hedgehog (SHH) pathway is activated in several types of malignancy and plays an important role in tumor cell proliferation and tumorigenesis. SHH binding to a 12-pass transmembrane receptor, Patched (PTCH), leads to freeing of Smoothened (SMO) and subsequent activation of GLI transcription factors. In the present study, we analyzed the expression of SHH, PTCH, SMO, and GLI1 in 31 follicular thyroid adenomas (FTA), 8 anaplastic thyroid carcinomas (ATC), and 51 papillary thyroid carcinomas (PTC) by immunohistochemical staining. More than 65% of FTA, PTC, and ATC specimens stained positive for SHH, PTCH, SMO, and GLI. However, the expression of the genes encoding these four molecules did not correlate with any clinicopathologic parameters, including the age, gender, the status ofBRAFgene mutation, tumor stage, local invasion, and metastasis. Three thyroid tumor cell lines (KAT-18, WRO82, and SW1736) all expressed the genes encoding these four molecules. 5-Bromo-2-deoxyuridine labeling and MTT cell proliferation assays revealed that cyclopamine (CP), an inhibitor of the SHH pathway, was able to inhibit the proliferation of KAT-18 and WRO82 cells more effectively than SW1736 cells. CP led to the arrest of cell cycle or apoptosis. Knockdown ofSHHandGLIexpression by miRNA constructs that targetSHHorGLImRNA in KAT-18 and SW1736 cells led to the inhibition of cell proliferation. Our results suggest that the SHH pathway is widely activated in thyroid neoplasms and may have potential as an early marker of thyroid cancer or as a potential therapeutic target for thyroid cancer treatment.

scholarly journals NKX6-1 mediates cancer stem-like properties and regulates sonic hedgehog signaling in leiomyosarcoma

2021 ◽  
Vol 28 (1) ◽  
Author(s):  
Po-Hsuan Su ◽  
Rui-Lan Huang ◽  
Hung-Cheng Lai ◽  
Lin-Yu Chen ◽  
Yu-Chun Weng ◽  
...  
Keyword(s):  
Tumor Growth ◽  
Sonic Hedgehog ◽  
Poor Prognosis ◽  
Cancer Genome ◽  
The Cancer Genome Atlas ◽  
Shh Pathway ◽  
Cancer Genome Atlas ◽  
Genome Atlas

Abstract Background Leiomyosarcoma (LMS), the most common soft tissue sarcoma, exhibits heterogeneous and complex genetic karyotypes with severe chromosomal instability and rearrangement and poor prognosis. Methods Clinical variables associated with NKX6-1 were obtained from The Cancer Genome Atlas (TCGA). NKX6-1 mRNA expression was examined in 49 human uterine tissues. The in vitro effects of NXK6-1 in LMS cells were determined by reverse transcriptase PCR, western blotting, colony formation, spheroid formation, and cell viability assays. In vivo tumor growth was evaluated in nude mice. Results Using The Cancer Genome Atlas (TCGA) and human uterine tissue datasets, we observed that NKX6-1 expression was associated with poor prognosis and malignant potential in LMS. NKX6-1 enhanced in vitro tumor cell aggressiveness via upregulation of cell proliferation and anchorage-independent growth and promoted in vivo tumor growth. Moreover, overexpression and knockdown of NKX6-1 were associated with upregulation and downregulation, respectively, of stem cell transcription factors, including KLF8, MYC, and CD49F, and affected sphere formation, chemoresistance, NOTCH signaling and Sonic hedgehog (SHH) pathways in human sarcoma cells. Importantly, treatment with an SHH inhibitor (RU-SKI 43) but not a NOTCH inhibitor (DAPT) reduced cell survival in NKX6-1-expressing cancer cells, indicating that an SHH inhibitor could be useful in treating LMS. Finally, using the TCGA dataset, we demonstrated that LMS patients with high expression of NKX6-1 and HHAT, an SHH pathway acyltransferase, had poorer survival outcomes compared to those without. Conclusions Our findings indicate that NKX6-1 and HHAT play critical roles in the pathogenesis of LMS and could be promising diagnostic and therapeutic targets for LMS patients.

scholarly journals 3-HAA Metabolic Pathway Regulates HCC Growth

2021 ◽  
Author(s):  
Zhaopeng Shi ◽  
Guifang Gan ◽  
Xianfu Gao ◽  
Fuxiang Chen ◽  
Jun Mi
Keyword(s):  
Tumor Growth ◽  
Metabolic Pathway ◽  
Tumor Formation ◽  
Aryl Hydrocarbon ◽  
Mechanistic Investigation ◽  
Tryptophan Metabolites ◽  
Hydroxyanthranilic Acid ◽  
Induced Apoptosis

Abstract Background Kynurenine, a metabolite of tryptophan, promotes immune tolerance in development and tumor evasion by binding to the aryl hydrocarbon receptor (AHR). However, the kynurenine catabolic enzyme IDO1 inhibitors fail in clinical trials. Methods The LC-MS/MS and GC-MS/MS were performed to measure the concentration of tryptophan metabolites. The PCX model, PDX model, and transposon liver cancer models were used to evaluate the effects of 3-HAA, DUSP6, and YY1 on HCC tumor formation and/or tumor growth. Results 3-hydroxyanthranilic acid (3-HAA) induced HCC apoptosis and reduced xenografted tumor growth, the survival of the transposon HCC mice, and synergized with IDO1 inhibitor on HCC growth in vivo. Overexpression of 3-HAA synthesis enzyme KMO suppressed tumor formation and tumor growth by increasing endogenous 3-HAA while adding exogenous 3-HAA also inhibited tumor growth. Notably, 3-HAA was lower in tumor cells due to the downregulation of its synthetic enzyme KMO/KYNU and/or upregulation of its catalytic enzyme HAAO. The mechanistic investigation demonstrated that 3-HAA induced dual-specificity phosphatase 6 (DUSP6) transcription. DUSP6 overexpression induced apoptosis of hepatocellular carcinoma (HCC) cells and suppressed the HCC growth in vitro and in vivo. DUSP6 knockdown abolished 3-HAA-induced apoptosis and restores tumor growth. Conclusions These findings demonstrate that 3-HAA metabolic pathway regulates HCC cell growth, suggesting it is a promising therapeutic candidate for HCC.

672: Regulation of Cavernous Nerve Injury-Induced Apoptosis by Sonic Hedgehog

2007 ◽  
Vol 177 (4S) ◽  
pp. 225-225
Author(s):  
Carol A. Podlasek ◽  
Yi Tang ◽  
Cynthia L. Meraz ◽  
Kevin E. McKenna ◽  
Kevin T. McVary
Keyword(s):  
Nerve Injury ◽  
Sonic Hedgehog ◽  
Cavernous Nerve ◽  
Induced Apoptosis ◽  
Cavernous Nerve Injury

scholarly journals PSIX-29 JAK2-STAT3 Pathway Mediated Satellite Cell Apoptosis to Govern Skeletal Muscle Growth with Lysine

2020 ◽  
Vol 98 (Supplement_4) ◽  
pp. 334-334
Author(s):  
Zhi-wen Song ◽  
Cheng-long Jin ◽  
Mao Ye ◽  
Chun-qi Gao ◽  
Hui-chao Yan ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Muscle Growth ◽  
Longissimus Dorsi ◽  
Control Group ◽  
Stat3 Pathway ◽  
Skeletal Muscle Growth ◽  
Longissimus Dorsi Muscle ◽  
Dorsi Muscle ◽  
Pathway Inhibition ◽  
Induced Apoptosis

Abstract Apoptosis is programmed cell death that can be stimulated by external stress or nutrition restrictions. Lysine (Lys) is an essential amino acid for pig growth, and the relationship between Lys deficiency caused apoptosis and inhibition of skeletal muscle growth remains unknown. The objective of this study was to investigate whether apoptosis could be regulated by Lys supplementation and the potential mechanism. In current work, 30 male Duroc × Landrace × Large weaned piglets were divided randomly into 3 groups: control group (Lys 1.30%), Lys deficiency group (Lys 0.86%), and Lys rescue group (Lys 0.86%, 0-14d; 1.30%,15–28 d). The experiment lasted for 28 days, and on the morning of 29 d, piglets were slaughtered to collect samples. Isobaric tag for relative and absolute quantification (iTRAQ) proteomics analysis of the longissimus dorsi muscle showed that Janus family tyrosine kinase (JAK)-signal transducer and activator of transcription (STAT) pathway was involved in Lys deficiency-induced apoptosis and inhibited skeletal muscle growth. Meanwhile, western blotting results of the longissimus dorsi muscle demonstrated that Lys deficiency caused apoptosis (P < 0.05) with the JAK2-STAT3 pathway inhibition (P < 0.05). Interestingly, apoptosis was suppressed (P < 0.05), and the JAK2-STAT3 pathway was reactivated (P < 0.05) after Lys re-supplementation in longissimus dorsi muscle. In addition, results of satellite cells (SCs) isolated from the longissimus dorsi muscle of 5-day-old Landrace piglets showed that Lys deficiency-induced apoptosis (P < 0.05) was mediated by the JAK2-STAT3 pathway inhibition (P < 0.05). Moreover, the JAK2-STAT3 pathway was reactivated (P < 0.05) by Lys re-supplementation and suppressed apoptosis in SCs (P < 0.05), and this effect was blocked (P < 0.05) after SCs treated with AG-490 (a specific inhibitor of JAK2). Collectively, Lys inhibited apoptosis in SCs to govern skeletal muscle growth via the JAK2-STAT3 pathway.

scholarly journals Sonic Hedgehog and Triiodothyronine Pathway Interact in Mouse Embryonic Neural Stem Cells

2020 ◽  
Vol 21 (10) ◽  
pp. 3672
Author(s):  
Pavel Ostasov ◽  
Jan Tuma ◽  
Pavel Pitule ◽  
Jiri Moravec ◽  
Zbynek Houdek ◽  
...  
Keyword(s):  
Stem Cells ◽  
Neural Stem Cells ◽  
Sonic Hedgehog ◽  
Shh Pathway ◽  
Proliferation Activity ◽  
The Central Nervous System ◽  
Beta Gene ◽  
Potential Tool ◽  
Receptor Beta ◽  
Transplantation Therapy

Neural stem cells are fundamental to development of the central nervous system (CNS)—as well as its plasticity and regeneration—and represent a potential tool for neuro transplantation therapy and research. This study is focused on examination of the proliferation dynamic and fate of embryonic neural stem cells (eNSCs) under differentiating conditions. In this work, we analyzed eNSCs differentiating alone and in the presence of sonic hedgehog (SHH) or triiodothyronine (T3) which play an important role in the development of the CNS. We found that inhibition of the SHH pathway and activation of the T3 pathway increased cellular health and survival of differentiating eNSCs. In addition, T3 was able to increase the expression of the gene for the receptor smoothened (Smo), which is part of the SHH signaling cascade, while SHH increased the expression of the T3 receptor beta gene (Thrb). This might be the reason why the combination of SHH and T3 increased the expression of the thyroxine 5-deiodinase type III gene (Dio3), which inhibits T3 activity, which in turn affects cellular health and proliferation activity of eNSCs.

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