GLI1 overexpression promotes gastric cancer cell proliferation and migration and induces drug resistance by combining with the AKT-mTOR pathway

Yao, Yizhou; Zhou, Diyuan; Shi, Daren; Zhang, Hui; Zhan, Shenghua; Shao, Xinyu; Sun, Kang; Sun, Liang; Wu, Guangting; Tian, Kangjun; Zhu, Xinguo; He, Songbing

doi:10.1016/j.biopha.2019.01.018

Cited by 44 publications

(41 citation statements)

References 32 publications

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“…The hedgehog pathway mediated by zinc finger protein GLI1 plays a major role in GC. However, Yao et al [37] demonstrated that the AKT/ mTOR pathway can activate GLI1. Moreover, the GLI1 and p-AKT expressions were correlated with tumor cell metastasis and drug resistance, and the expression level was negatively correlated with the prognosis of patients with GC.…”

Section: The Tumors Of Digestive Systemmentioning

confidence: 99%

mTOR signaling pathway and mTOR inhibitors in cancer: progress and challenges

et al. 2020

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Mammalian target of rapamycin (mTOR) regulates cell proliferation, autophagy, and apoptosis by participating in multiple signaling pathways in the body. Studies have shown that the mTOR signaling pathway is also associated with cancer, arthritis, insulin resistance, osteoporosis, and other diseases. The mTOR signaling pathway, which is often activated in tumors, not only regulates gene transcription and protein synthesis to regulate cell proliferation and immune cell differentiation but also plays an important role in tumor metabolism. Therefore, the mTOR signaling pathway is a hot target in anti-tumor therapy research. In recent years, a variety of newly discovered mTOR inhibitors have entered clinical studies, and a variety of drugs have been proven to have high activity in combination with mTOR inhibitors. The purpose of this review is to introduce the role of mTOR signaling pathway on apoptosis, autophagy, growth, and metabolism of tumor cells, and to introduce the research progress of mTOR inhibitors in the tumor field.

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Section: The Tumors Of Digestive Systemmentioning

confidence: 99%

mTOR signaling pathway and mTOR inhibitors in cancer: progress and challenges

et al. 2020

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“…Indeed, GLI1 was shown to activate the expression of genes involved in multiple cellular functions, including cell proliferation (cyclin D1/D2 and FOXM1) [24, 25], angiogenesis (VEGF family) [26], epithelial-mesenchymal transition (SNAI1) [27], and invasion (osteopontin and MMP) [28–30]. Furthermore, GLI1 exerts its function through crosstalk with several non-canonical Hh signaling, such as mTOR [31, 32], KRAS [33], TGFβ [34, 35], and WNT [36, 37]. Therefore, GLI1 is emerging as a promising target for blocking Hh signaling and treating cancer.…”

Section: Introductionmentioning

confidence: 99%

The role of hedgehog signaling in gastric cancer: molecular mechanisms, clinical potential, and perspective

Song

Wang

et al. 2019

Cell Commun Signal

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Patients with advanced gastric cancer usually have a poor prognosis and limited therapeutic options. Overcoming this challenge requires novel targets and effective drugs. The Hedgehog (Hh) signaling pathway plays a crucial role in the development of the gastrointestinal tract and maintenance of the physiologic function of the stomach. Aberrantly activated Hh signaling is implicated in carcinogenesis as well as maintenance of cancer stem cells. Somatic mutations in the components of Hh signaling (PTCH1 and SMO) have been shown to be a major cause of basal cell carcinoma, and dozens of Hh inhibitors have been developed. To date, two inhibitors (GDC-0449 and LDE225) have been approved by the U.S. Food and Drug Administration to treat basal cell carcinoma and medulloblastoma. Here, we review the role of the Hh signaling in the carcinogenesis and progression of gastric cancer and summarize recent findings on Hh inhibitors in gastric cancer. Hedgehog signaling is often aberrantly activated and plays an important role during inflammation and carcinogenesis of gastric epithelial cells. Further study of the precise mechanisms of Hh signaling in this disease is needed for the validation of therapeutic targets and evaluation of the clinical utility of Hh inhibitors for gastric cancer.

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“…In gastric cancer, the deregulated Shh pathway with activation of Gli transcription factors enhances the migration and metastasis as well as induces drug resistance. Yao et al suggested that coexpression of Gli1 and p-AKT in gastric cancer associated with invasion and drug resistance [36]. In another study, Yu et al showed that genistein inhibits gastric cancer stem cell proliferation by reducing Gli1 and CD44 mRNA and protein expression levels [37].…”

Section: Discussionmentioning

confidence: 99%

Efficacy of Metformin and Chemotherapeutic Agents on the Inhibition of Colony Formation and Shh/Gli1 Pathway: Metformin/Docetaxel Versus Metformin/5-Fluorouracil

et al. 2020

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Background Gastric cancer is a common gastrointestinal cancer characterized by poor prognosis and chemoresistance. Docetaxel and 5-fluorouracil (5-FU) are frequently used for the treatment of gastric cancer. Despite their potent anti-cancer effects, chemoresistance occurs in metastatic gastric cancer. Metformin, a popular anti-diabetic drug, has been proven to have potent anticancer effects on gastrointestinal cancers. Here, we aim to improve this chemotherapy agents’ efficacy by pretreatment with metformin. Methods The AGS gastric cancer cell line were pretreated with three different sub-toxic concentration of metformin and then treated with various concentrations of 5-FU and docetaxel.The anticancer effects of the combination of metformin with the chemotherapy agents were determined using clonogenic assay and DAPi staining. We used real-time PCR to evaluate Gli1, Gli2, and TWIST1 mRNA expression levels in the gastric cancer cells. Also, the expression of the Shh protein was assessed using immunocytochemistry. Results Here, we found that metformin sensitized the gastric cancer cells to chemotherapy. The combination treatments were more effective in reducing the number of cancer colonies compared to 5-FU or docetaxel alone. The combination of metformin with 5-FU or docetaxel significantly reduced the number of cells expressing the Shh protein compared to the 5-FU alone or docetaxel alone. Interestingly, we found that the combination of metformin with docetaxel significantly down-regulated the mRNA levels of Gli1, Gli2, and TWIST1 in the AGS gastric cancer cell line compared to docetaxel alone. Conclusion Overall, our data strongly support an important role for metformin as an enhancer of the efficacy of chemotherapeutic agents against gastric cancer.

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GLI1 overexpression promotes gastric cancer cell proliferation and migration and induces drug resistance by combining with the AKT-mTOR pathway

Cited by 44 publications

References 32 publications

mTOR signaling pathway and mTOR inhibitors in cancer: progress and challenges

mTOR signaling pathway and mTOR inhibitors in cancer: progress and challenges

The role of hedgehog signaling in gastric cancer: molecular mechanisms, clinical potential, and perspective

Efficacy of Metformin and Chemotherapeutic Agents on the Inhibition of Colony Formation and Shh/Gli1 Pathway: Metformin/Docetaxel Versus Metformin/5-Fluorouracil

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