ICG-001 suppresses growth of gastric cancer cells and reduces chemoresistance of cancer stem cell-like population

Journal of Experimental & Clinical Cancer Research, Sep 2017

ICG-001, a small molecule, binds CREB-binding protein (CBP) to disrupt its interaction with β-catenin and inhibits CBP function as a co-activator of Wnt/β-catenin-mediated transcription. Given its ability to inhibit Wnt/β-catenin signaling pathway, ICG-001 has been used in some tumor types to exert its anticarcinogenic effect. Here, we examined ICG-001 and its potential role as a therapeutic in gastric cancer (GC). The gastric cancer cell lines SGC-7901, MGC-803, BGC-823 and MKN-45 were used in vitro and in vivo. The abilities of cell proliferation, tumor sphere formation, metastasis, tumorgenesis and chemoresistance to chemotherapy drugs in vitro were evaluated by MTT assay, colony formation assay, flow cytometry, migration and invasion assay, and tumor spheres culture. The in vivo experiments were performed using a subcutaneous transplantation tumor model in athymic nude mice. Alterations at RNA and protein levels were followed by qRT-PCR, western blot, coimmunoprecipitations and immunofluorescence assay. In this study, we showed that ICG-001 significantly inhibited growth and metastasis of multiple GC cell lines, induced cell apoptosis, and augmented in vitro tumor spheres suppression when used in combination with chemotherapy drugs probably through robustly blocking association of β-catenin with CBP and N-cadherin, but promoting association of β-catenin with P300 and E-cadherin, instead of altering the distribution and expression of β-catenin. Our findings suggest that ICG-001 suppresses GC cell line growth, metastasis and reduces its stem cell-like properties and chemoresistance, indicating that ICG-001 is a potentially useful small molecule therapeutic for GC.

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ICG-001 suppresses growth of gastric cancer cells and reduces chemoresistance of cancer stem cell-like population

Liu et al. Journal of Experimental & Clinical Cancer Research ICG-001 suppresses growth of gastric cancer cells and reduces chemoresistance of cancer stem cell-like population Yi Liu 0 Hui Chen 0 Peiming Zheng Yingxia Zheng Qin Luo Guohua Xie Yanhui Ma Lisong Shen 0 Equal contributors Department of Clinical Laboratory, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine , Shanghai 200092 , China Background: ICG-001, a small molecule, binds CREB-binding protein (CBP) to disrupt its interaction with β-catenin and inhibits CBP function as a co-activator of Wnt/β-catenin-mediated transcription. Given its ability to inhibit Wnt/ β-catenin signaling pathway, ICG-001 has been used in some tumor types to exert its anticarcinogenic effect. Here, we examined ICG-001 and its potential role as a therapeutic in gastric cancer (GC). Methods: The gastric cancer cell lines SGC-7901, MGC-803, BGC-823 and MKN-45 were used in vitro and in vivo. The abilities of cell proliferation, tumor sphere formation, metastasis, tumorgenesis and chemoresistance to chemotherapy drugs in vitro were evaluated by MTT assay, colony formation assay, flow cytometry, migration and invasion assay, and tumor spheres culture. The in vivo experiments were performed using a subcutaneous transplantation tumor model in athymic nude mice. Alterations at RNA and protein levels were followed by qRT-PCR, western blot, coimmunoprecipitations and immunofluorescence assay. Results: In this study, we showed that ICG-001 significantly inhibited growth and metastasis of multiple GC cell lines, induced cell apoptosis, and augmented in vitro tumor spheres suppression when used in combination with chemotherapy drugs probably through robustly blocking association of β-catenin with CBP and N-cadherin, but promoting association of β-catenin with P300 and E-cadherin, instead of altering the distribution and expression of β-catenin. Conclusions: Our findings suggest that ICG-001 suppresses GC cell line growth, metastasis and reduces its stem cell-like properties and chemoresistance, indicating that ICG-001 is a potentially useful small molecule therapeutic for GC. ICG-001; Gastric cancer; Wnt/β-catenin signaling pathway; Growth; Stem cell-like Background Gastric cancer (GC) is currently the fourth most common malignancy and the third leading cause of cancerrelated deaths worldwide [ 1 ]. The incidence and mortality of gastric cancer are the highest in East Asia (particularly in Korea, Mongolia, Japan, and China), and it has become the second most lethal cancer in China [ 2 ]. GC is difficult to treat because it frequently presents at an advanced, non-operative stage and is highly resistant to cytotoxic or targeted molecular therapy. While our understanding of the molecular and cellular basis of GC continues to expand, present therapeutic options remain limited and offer only modest survival benefits for most patients. Wnt/β-catenin signaling pathway is a critical developmental signaling pathway whose deregulation is strongly implicated in the pathogenesis of many types of cancer [ 3 ]. Perturbations of Wnt/β-catenin signaling pathway can promote the initiation and progression of GC and has been linked to aggressive tumor behavior [ 4 ]. Although plagued by poor pharmacokinetics in vivo, several novel Wnt/β-catenin inhibitors have been demonstrable in vivo activity and are now in various stages of preclinical or early clinical development. ICG-001 was first identified in a screen of small molecules that inhibited Wnt/β-catenin transcriptional activity in a colorectal cancer cell line [ 5 ]. ICG-001 selectively blocks the interaction of β-catenin with its transcriptional co-activator cyclic-AMP-responseelement-binding protein (CBP). Recent studies have provided convincing evidence of the inhibitory effects of ICG-001 on Wnt-driven disease models including pulmonary fibrosis [ 6 ], renal interstitial fibrosis [ 7 ], acute lymphoblastic leukemia [ 8 ], chronic myocardial infarction [ 9 ], dermal fibrosis [ 10 ], salivary tumorigenesis [ 11 ] and pancreatic ductal adenocarcinoma [ 12 ]. However, ICG001 has not been explored in gastric cancer. Further, the mechanisms of ICG-001 in cancer inhibition and in chemoresistance of cancer stem cells to chemotherapy drugs are not yet fully discovered. Given the importance of Wnt/β-catenin signaling pathway in GC, we have now explored therapeutic potential and related mechanism of ICG-001 in GC cell lines and stem-like cells. ICG-001 significantly inhibited in vitro and in vivo GC cell lines growth by inducing G0/G1 cell cycle arrest and reduced chemoresistance of stem-like cells to chemotherapy drugs. Mechanically, ICG-001 disrupted the association between β-catenin with CBP, P300, E-cadherin and N-cadherin, instead of perturbing the expression and distribution of β-catenin. Methods Cell culture and treatment The gastric cancer cell lines SGC-7901, MGC-803, BGC-823 and MKN-45 were purcha (...truncated)


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Yi Liu, Hui Chen, Peiming Zheng, Yingxia Zheng, Qin Luo, Guohua Xie, Yanhui Ma, Lisong Shen. ICG-001 suppresses growth of gastric cancer cells and reduces chemoresistance of cancer stem cell-like population, Journal of Experimental & Clinical Cancer Research, 2017, pp. 125, DOI: 10.1186/s13046-017-0595-0