Effects and mechanisms of blocking the hedgehog signaling pathway in human gastric cancer cells

Gu, Hongchen; Li, X U; Cong-zhi, Zhou; Wen, Yu-ming; Shen, Yang; Zhou, Lisheng; Li, Jikun

doi:10.3892/ol.2015.3032

Cited by 8 publications

(7 citation statements)

References 36 publications

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“…In contrast, the Hh signalling in the hepatocytes from the C57BL/6N mice was blocked for only 24 h after preparation in the 2D cell culture; therefore, they were exposed to impaired Hh signalling for a much shorter time and were not exposed to systemic effects. Unfortunately, we could not detect significant downregulation of Gli1 and Ptch1 in primary hepatocytes treated with cyclopamine for 24 h as it is known for numerous other cell types [35,36]. Several reasons for this apparent discrepancy are discussed below.…”

Section: Hh/mtor Crosstalk In Hepatocytesmentioning

confidence: 69%

Cyclopamine and Rapamycin Synergistically Inhibit mTOR Signalling in Mouse Hepatocytes, Revealing an Interaction of Hedgehog and mTor Signalling in the Liver

Spormann

Rennert

Kolbe

et al. 2020

Cells

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In the liver, energy homeostasis is mainly regulated by mechanistic target of rapamycin (mTOR) signalling, which influences relevant metabolic pathways, including lipid metabolism. However, the Hedgehog (Hh) pathway is one of the newly identified drivers of hepatic lipid metabolism. Although the link between mTOR and Hh signalling was previously demonstrated in cancer development and progression, knowledge of their molecular crosstalk in healthy liver is lacking. To close this information gap, we used a transgenic mouse model, which allows hepatocyte-specific deletion of the Hh pathway, and in vitro studies to reveal interactions between Hh and mTOR signalling. The study was conducted in male and female mice to investigate sexual differences in the crosstalk of these signalling pathways. Our results reveal that the conditional Hh knockout reduces mitochondrial adenosine triphosphate (ATP) production in primary hepatocytes from female mice and inhibits autophagy in hepatocytes from both sexes. Furthermore, in vitro studies show a synergistic effect of cyclopamine and rapamycin on the inhibition of mTor signalling and oxidative respiration in primary hepatocytes from male and female C57BL/6N mice. Overall, our results demonstrate that the impairment of Hh signalling influences mTOR signalling and therefore represses oxidative phosphorylation and autophagy.

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Section: Hh/mtor Crosstalk In Hepatocytesmentioning

confidence: 69%

Cyclopamine and Rapamycin Synergistically Inhibit mTOR Signalling in Mouse Hepatocytes, Revealing an Interaction of Hedgehog and mTor Signalling in the Liver

Spormann

Rennert

Kolbe

et al. 2020

Cells

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“…Previous studies have shown that HH signaling plays a pivotal role in regulating cell migration [46]. There, we examined the potential effect of HHIP over-expression on GC cell migration with the “Transwell” assay.…”

Section: Resultsmentioning

confidence: 99%

Inhibition of HHIP Promoter Methylation Suppresses Human Gastric Cancer Cell Proliferation and Migration

Zuo

Qian

et al. 2018

Cell Physiol Biochem

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Background/Aims: Human hedgehog-interacting protein (HHIP) is a negative regulator of the hedgehog (HH) signaling pathway. It is deregulated in gastric cancer. The underlying molecular mechanism of HHIP-induced inhibition of HH signaling remains to be determined. Methods: A lentiviral HHIP expression vector (“LV-HHIP”) was established to exogenously over-express HHIP in gastric cancer cells. HHIP protein and mRNA were tested by Western blotting assay and quantitative real-time PCR assay, respectively. Cell survival was tested by the Cell Counting Kit-8 (CCK-8) assay. Cell proliferation was examined by the BrdU ELISA assay and [H³] Thymidine DNA incorporation assay. Cell invasion and migration were tested by the phagokinetic track assay and the “Transwell” assay. The bisulfite-sequencing PCR was applied to test HHIP promoter methylation. Results: In the established (AGS cell line) and primary human gastric cancer cells, LV-HHIP transfection increased HHIP expression and inhibited cancer cell survival and proliferation as well as cell migration and invasion. Furthermore, LV-HHIP significantly attenuated promoter methylation of the endogenous HHIP gene in AGS cells, causing it upregulation. Inhibition of methylation by 5-aza-dc similarly induced HHIP expression in gastric cancer cells, which inhibited cancer cell proliferation and migration. Conclusions: Our results suggest that inhibition of HHIP promoter methylation can efficiently inhibit human gastric cancer cell proliferation and migration.

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“…More inhibitors have been developed to target SMO than SHH or GLI. Cyclopamine, the first reported SMO inhibitor, exhibits inhibitory activity in vitro gastrointestinal tumors models 33 , 49 , 50 . Saridegib (IPI-926), a semisynthetic analog of cyclopamine, with improved chemical stability and biological activity, has entered a phase I clinical trial for the treatment of gastric cancer 144 .…”

Section: Hh Signaling As a Potential Clinical Prognostic And Therapeumentioning

confidence: 99%

“…HH inhibitors that have been effective in treating gastrointestinal tumors include isoflavone 30 , 31 , imiquimod 32 and 5E1 33 . SMO inhibitors that have been effective in treating gastrointestinal tumors include vismodegib 29 , 34 , 35 , vitamin D3 36 , 37 , 38 , BMS-833923 39 , TAK-441 40 , saridegib 41 , itraconazole 42 , 43 , 44 , miR-218 45 , 46 , 47 , MS-0022 48 , cyclopamine 33 , 49 , 50 and KAAD-cyclopamine 51 . GLI inhibitors that have been effective in treating gastrointestinal tumors include curcumin 52 , 53 , 54 , resveratrol 55 , 56 , epigallocatechin-3-gallatel 57 , 58 , arsenic trioxide 59 , 60 , 61 , GANT 61 62 , 63 , 64 , zerumbone 65 , sodium arsenite 66 and AY9944 67 .…”

Section: Introductionmentioning

confidence: 99%

Hedgehog signaling in gastrointestinal carcinogenesis and the gastrointestinal tumor microenvironment

Zhang

Fan

Zeng

et al. 2021

Acta Pharmaceutica Sinica B

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The Hedgehog (HH) signaling pathway plays important roles in gastrointestinal carcinogenesis and the gastrointestinal tumor microenvironment (TME). Aberrant HH signaling activation may accelerate the growth of gastrointestinal tumors and lead to tumor immune tolerance and drug resistance. The interaction between HH signaling and the TME is intimately involved in these processes, for example, tumor growth, tumor immune tolerance, inflammation, and drug resistance. Evidence indicates that inflammatory factors in the TME, such as interleukin 6 (IL-6) and interferon- γ (IFN- γ ), macrophages, and T cell-dependent immune responses, play a vital role in tumor growth by affecting the HH signaling pathway. Moreover, inhibition of proliferating cancer-associated fibroblasts (CAFs) and inflammatory factors can normalize the TME by suppressing HH signaling. Furthermore, aberrant HH signaling activation is favorable to both the proliferation of cancer stem cells (CSCs) and the drug resistance of gastrointestinal tumors. This review discusses the current understanding of the role and mechanism of aberrant HH signaling activation in gastrointestinal carcinogenesis, the gastrointestinal TME, tumor immune tolerance and drug resistance and highlights the underlying therapeutic opportunities.

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Effects and mechanisms of blocking the hedgehog signaling pathway in human gastric cancer cells

Cited by 8 publications

References 36 publications

Cyclopamine and Rapamycin Synergistically Inhibit mTOR Signalling in Mouse Hepatocytes, Revealing an Interaction of Hedgehog and mTor Signalling in the Liver

Cyclopamine and Rapamycin Synergistically Inhibit mTOR Signalling in Mouse Hepatocytes, Revealing an Interaction of Hedgehog and mTor Signalling in the Liver

Inhibition of HHIP Promoter Methylation Suppresses Human Gastric Cancer Cell Proliferation and Migration

Hedgehog signaling in gastrointestinal carcinogenesis and the gastrointestinal tumor microenvironment

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