scholarly journals Rhein Suppresses Colorectal Cancer Cell Growth by Inhibiting the mTOR Pathway In Vitro and In Vivo

Cancers ◽  
2021 ◽  
Vol 13 (9) ◽  
pp. 2176
Author(s):  
Haibo Zhang ◽  
Jun-Koo Yi ◽  
Hai Huang ◽  
Song Park ◽  
Sijun Park ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cell Cycle ◽  
Cell Migration ◽  
Cell Growth ◽  
Anticancer Activity ◽  
Migration And Invasion ◽  
Mtor Signaling Pathway ◽  
Underlying Mechanisms

Colorectal cancer (CRC) is one of the leading causes of mortality and morbidity in the world. Rhein has demonstrated therapeutic effects in various cancer models. However, its effects and underlying mechanisms of action in CRC remain poorly understood. We investigated the potential anticancer activity and underlying mechanisms of rhein in CRC in vitro and in vivo. Cell viability and anchorage-independent colony formation assays were performed to examine the antigrowth effects of rhein on CRC cells. Wound-healing and Transwell assays were conducted to assess cell migration and invasion capacity. Cell cycle and apoptosis were investigated by flow cytometry and verified by immunoblotting. A tissue microarray was used to detect mTOR expression in CRC patient tissues. Gene overexpression and knockdown were done to analyze the function of mTOR in CRC. The anticancer effect of rhein in vivo was assessed in a CRC xenograft mouse model. The results show that rhein significantly inhibited CRC cell growth by inducing S-phase cell cycle arrest and apoptosis. Rhein inhibited CRC cell migration and invasion through the epithelial–mesenchymal transition (EMT) process. mTOR was highly expressed in CRC cancer tissues and cells. Overexpression of mTOR promoted cell growth, migration, and invasion, whereas mTOR knockdown diminished these phenomena in CRC cells in vitro. In addition, rhein directly targeted mTOR and inhibited the mTOR signaling pathway in CRC cells. Rhein promoted mTOR degradation through the ubiquitin-proteasome pathway. Intraperitoneal administration of rhein inhibited HCT116 xenograft tumor growth through the mTOR pathway. In conclusion, rhein exerts anticancer activity in vitro and in vivo by targeting mTOR and inhibiting the mTOR signaling pathway in CRC. Our results indicate that rhein is a potent anticancer agent that may be useful for the prevention and treatment of CRC.

scholarly journals Natural compound rhein suppresses colorectal cancer cells growth through mTOR/p70S6 kinase pathway in vitro and in vivo

2020 ◽  
Author(s):  
Haibo Zhang ◽  
Song Park ◽  
Hai Huang ◽  
Jun koo Yi ◽  
Sijun Park ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cell Cycle ◽  
Cell Migration ◽  
Cell Growth ◽  
Signaling Pathway ◽  
Migration And Invasion ◽  
P70s6 Kinase ◽  
Cell Migration And Invasion

Abstract Background: Rhein is a natural agent isolated from the traditional Chinese medicine rhubarb, which has been used as a medicine in China since ancient times. Although rhein was found to have significant anticancer effects in different cancer models, the effect and the underlying mechanisms of action of rhein in colorectal cancer (CRC) remain unclear. The mTOR/p70S6 kinase (p70S6K) pathway has been demonstrated as an attractive target for developing novel cancer therapeutics.Methods: The human CRC cell lines HCT116, HCT15, and DLD1 and xenograft mice were used in this study to investigate the effects of rhein. Assessments of cellular morphology, cell proliferation, and anchorage-independent colony formation were performed to examine the effects of rhein on cell growth. Wound healing assay and transwell migration and invasion assay were conducted to detect cell migration and invasion. Cell cycle and apoptosis were investigated by flow cytometry and verified by immunoblotting. Tissue microarray was used to detect mTOR expression in patients with CRC. Gene overexpression and knockdown were implemented to analyze the function of mTOR in CRC. The in vivo effect of rhein was assessed in a xenograft mouse model.Results: Rhein significantly inhibited CRC cell growth by inducing S phase cell cycle arrest and apoptosis. It also inhibited CRC cell migration and invasion ability through EMT process. mTOR was highly expression in CRC cancer tissues and cells exhibited high mTOR expression. Overexpression of mTOR promoted cell growth, migration, and invasion ability, whereas mTOR knockdown diminished these phenomena of CRC cells in vitro. Moreover, rhein directly targeted mTOR and suppressed the mTOR/p70S6K signaling pathway in CRC cells. Intraperitoneal administration of rhein inhibited CRC cell HCT116 xenograft tumor growth through the mTOR/p70S6K pathway.Conclusions: Rhein exerted anticancer activity in vitro and in vivo through directly targeting mTOR and inhibiting mTOR/p70S6K signaling pathway. These data indicate that rhein is a potent anticancer agent that could be useful for the prevention or treatment of CRC.

PGM1 Suppresses Colorectal Cancer Cell Migration And Invasion by Regulating PI3K/ AKT Pathway

2021 ◽  
Author(s):  
Zhewen Zheng ◽  
Xue Zhang ◽  
Jian Bai ◽  
Long Long ◽  
Di Liu ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cell Cycle ◽  
Colony Formation ◽  
Tumor Formation ◽  
Akt Pathway ◽  
Migration And Invasion ◽  
Cycle Arrest ◽  
Cancer Pathogenesis

Abstract BackgroundPhosphoglucomutase 1(PGM1) is known for its involvement in cancer pathogenesis. However, its biological role in colorectal cancer (CRC) is unknown. Here, we studied the functions and mechanisms of PGM1 in CRC.Methods We verified PGM-1 as a DEG by a comprehensive strategy of the TCGA-COAD dataset mining and computational biology. Relative levels of PGM-1 in CRC tumors and adjoining peritumoral tissue were identified by qRT-PCR, WB, and IHC staining in a tissue microarray. PGM1 functions were analyzed using CCK8, EdU, colony formation, cell cycle, apoptosis, and Transwell migration and invasion assays. The influence of PGM1 was further investigated using tumor formation in vivo.ResultsPGM1 mRNA and protein were both reduced in CRC and the reduction was related to CRC pathology and overall survival. PGM1 knockdown stimulated both proliferation and colony formation, promoting cell cycle arrest and apoptosis while overexpression has opposite effects in CRC cells both in vivo and in vitro. Furthermore, we lined the actions of PGM1 to the PI3K/ AKT pathway. ConclusionWe verified that PGM1 suppresses CRC through the PI3K/ AKT pathway. These results suggest the potential for targeting PGM1 in CRC therapies.

scholarly journals MicroRNA-139-3p Suppresses Tumor Growth and Metastasis in Hepatocellular Carcinoma by Repressing ANXA2R

2018 ◽  
Vol 26 (9) ◽  
pp. 1391-1399 ◽  
Author(s):  
Zeng Cheng Zou ◽  
Min Dai ◽  
Zeng Yin Huang ◽  
Yi Lu ◽  
He Ping Xie ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Cell Migration ◽  
Cell Growth ◽  
Mouse Model ◽  
Migration And Invasion ◽  
Tumor Growth And Metastasis ◽  
Underlying Mechanisms ◽  
Hcc Cells

The direct roles of miR-139-3p on hepatocellular carcinoma (HCC) cell growth and metastasis remain poorly understood. We attempted to demonstrate the regulatory role of miR-139-3p in HCC progression and its underlying mechanisms. Here we showed that miR-139-3p expression was significantly reduced in the HCC tissues compared to paratumor tissues. Exogenous overexpression of miR-139-3p inhibited the migration and invasion of HCC cells, whereas downregulation of miR-139-3p was able to induce HCC HepG2 and SNU-449 cell migration and invasion. In addition, miR-139-3p inhibited HCC growth and lung metastasis in an in vivo mouse model, which is mainly regulated by annexin A2 receptor (ANXA2R). Finally, we identified that the expression of miR-139-3p was inversely correlated with ANXA2R expression in human HCC tissue. All these results demonstrated that miR-139-3p inhibited the metastasis process in HCC by downregulating ANXA2R expression.

scholarly journals Targeting AKT with costunolide suppresses the growth of colorectal cancer cells and induces apoptosis in vitro and in vivo

2021 ◽  
Vol 40 (1) ◽  
Author(s):  
Hai Huang ◽  
Song Park ◽  
Haibo Zhang ◽  
Sijun Park ◽  
Wookbong Kwon ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Colon Cancer ◽  
Cell Proliferation ◽  
Cell Growth ◽  
The Body ◽  
Migration And Invasion ◽  
Regulation Mechanism ◽  
Mesenchymal Transformation

Abstract Background Colorectal cancer (CRC) is a clinically challenging malignant tumor worldwide. As a natural product and sesquiterpene lactone, Costunolide (CTD) has been reported to possess anticancer activities. However, the regulation mechanism and precise target of this substance remain undiscovered in CRC. In this study, we found that CTD inhibited CRC cell proliferation in vitro and in vivo by targeting AKT. Methods Effects of CTD on colon cancer cell growth in vitro were evaluated in cell proliferation assays, migration and invasion, propidium iodide, and annexin V-staining analyses. Targets of CTD were identified utilizing phosphoprotein-specific antibody array; Costunolide-sepharose conjugated bead pull-down analysis and knockdown techniques. We investigated the underlying mechanisms of CTD by ubiquitination, immunofluorescence staining, and western blot assays. Cell-derived tumour xenografts (CDX) in nude mice and immunohistochemistry were used to assess anti-tumour effects of CTD in vivo. Results CTD suppressed the proliferation, anchorage-independent colony growth and epithelial-mesenchymal transformation (EMT) of CRC cells including HCT-15, HCT-116 and DLD1. Besides, the CTD also triggered cell apoptosis and cell cycle arrest at the G2/M phase. The CTD activates and induces p53 stability by inhibiting MDM2 ubiquitination via the suppression of AKT’s phosphorylation in vitro. The CTD suppresses cell growth in a p53-independent fashion manner; p53 activation may contribute to the anticancer activity of CTD via target AKT. Finally, the CTD decreased the volume of CDX tumors without of the body weight loss and reduced the expression of AKT-MDM2-p53 signaling pathway in xenograft tumors. Conclusions Our project has uncovered the mechanism underlying the biological activity of CTD in colon cancer and confirmed the AKT is a directly target of CTD. All of which These results revealed that CTD might be a new AKT inhibitor in colon cancer treatment, and CTD is worthy of further exploration in preclinical and clinical trials.

scholarly journals IGHG1 Regulates Prostate Cancer Growth via the MEK/ERK/c-Myc Pathway

2019 ◽  
Vol 2019 ◽  
pp. 1-10 ◽  
Author(s):  
Jing Chu ◽  
Yutong Li ◽  
Zhihai Deng ◽  
Zhenlin Zhang ◽  
Qun Xie ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cell Cycle ◽  
Cell Growth ◽  
Heavy Chain ◽  
Cancer Growth ◽  
Prostate Cancer Cells ◽  
Cycle Arrest ◽  
Underlying Mechanisms

Increasing evidence indicates that immunoglobulins are important for the regulation of various cancers including prostate cancer (PCa). However, the underlying mechanisms of IgG regulated PCa development remain to be further explored. Here, we demonstrated that IgG1 heavy chain (IGHG1) was increased in tissues from PCa patients. Inhibition of IGHG1 by antibody blocking or genetic knockdown suppressed cell growth and induced cell cycle arrest and ultimate apoptosis. Expression levels of c-Myc were positively correlated with the levels of IGHG1. Furthermore, MEK/ERK/c-Myc pathway lied downstream of IGHG1 in cultured prostate cancer cells. Inhibition of IGHG1 restrained the tumor growth in nude mice and inactivated MEK/ERK/c-Myc pathway both in vitro and in vivo. These findings suggest that IGHG1 play a crucial role during the development of prostate cancer and inhibition of IGHG1 may be a potential therapy in the treatment of PCa.

scholarly journals RANK promotes colorectal cancer migration and invasion by activating the Ca2+-calcineurin/NFATC1-ACP5 axis

2021 ◽  
Vol 12 (4) ◽  
Author(s):  
Qian Liang ◽  
Yun Wang ◽  
Yingsi Lu ◽  
Qingqing Zhu ◽  
Wenlin Xie ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cell Migration ◽  
Nuclear Translocation ◽  
Migration And Invasion ◽  
Tartrate Resistant Acid Phosphatase ◽  
Activated T Cells ◽  
Cell Migration And Invasion ◽  
Cell Metastasis

AbstractThe tumor necrosis factor (TNF) receptor superfamily member 11a (TNFRSF11a, also known as RANK) was demonstrated to play an important role in tumor metastasis. However, the specific function of RANK in colorectal cancer (CRC) metastasis and the underlying mechanism are unknown. In this study, we found that RANK expression was markedly upregulated in CRC tissues compared with that in matched noncancerous tissues. Increased RANK expression correlated positively with metastasis, higher TNM stage, and worse prognosis in patients with CRC. Overexpression of RANK promoted CRC cell metastasis in vitro and in vivo, while knockdown of RANK decreased cell migration and invasion. Mechanistically, RANK overexpression significantly upregulated the expression of tartrate-resistant acid phosphatase 5 (TRAP/ACP5) in CRC cells. Silencing of ACP5 in RANK-overexpressing CRC cells attenuated RANK-induced migration and invasion, whereas overexpression of ACP5 increased the migration and invasion of RANK-silencing cells. The ACP5 expression was transcriptionally regulated by calcineurin/nuclear factor of activated T cells c1 (NFATC1) axis. The inhibition of calcineurin/NFATC1 significantly decreased ACP5 expression, and attenuated RANK-induced cell migration and invasion. Furthermore, RANK induced phospholipase C-gamma (PLCγ)-mediated inositol-1,4,5-trisphosphate receptor (IP3R) axis and stromal interaction molecule 1 (STIM1) to evoke calcium (Ca2+) oscillation. The RANK-mediated intracellular Ca2+ mobilization stimulated calcineurin to dephosphorylate NFATC1 and induce NFATC1 nuclear translocation. Both blockage of PLCγ-IP3R axis and STIM1 rescued RANK-induced NFATC1 nuclear translocation, ACP5 expression, and cell metastasis. Our study revealed the functional expression of RANK in human CRC cells and demonstrated that RANK induced the Ca2+-calcineurin/NFATC1-ACP5 axis in the regulation of CRC metastasis, that might be amenable to therapeutic targeting.

scholarly journals LncRNA LINC00337 sponges mir-1285-3p to promote proliferation and metastasis of lung adenocarcinoma cells by upregulating YTHDF1

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Ru-nan Zhang ◽  
Dong-mei Wu ◽  
Li-ping Wu ◽  
Guo-wei Gao
Keyword(s):  
Cell Cycle ◽  
Cell Proliferation ◽  
Lung Adenocarcinoma ◽  
Molecular Mechanisms ◽  
Luciferase Reporter ◽  
Migration And Invasion ◽  
Gear Up ◽  
Underlying Mechanisms

Abstract Background Emerging studies have shown that long noncoding RNAs (lncRNAs) predominantly function in the carcinogenesis of multiple developing human tumors. The current study aimed to investigate the underlying mechanisms of LINC00337 in lung adenocarcinoma. Methods We analyzed TCGA and GTEx datasets and chose LINC00337 as the research object. Cell proliferation, cell apoptosis, cell cycle, migration, and invasion were detected in the gain and loss experiments of LINC00337 both in vitro and in vivo. Moreover, RNA pull-down, luciferase reporter assays, western blotting analysis, and rescue experiments were performed to investigate the underlying molecular mechanisms of LINC00337 function. Results LINC00337 expression was remarkably upregulated in lung adenocarcinoma. In addition, LINC00337 knockdown was shown to repress cell migration, invasion, and proliferation, as well as the cell cycle, and gear up apoptosis in lung adenocarcinoma in vitro and in vivo. With respect to the mechanism, LINC00337 knockdown boosted miR-1285-3p expression and then restrained YTHDF1 expression post-transcriptionally. Crucially, both miR-1285-3p decrement and YTHDF1 overexpression successfully reversed the influence on cell proliferation, migration, invasion, and apoptosis caused by LINC00337 shRNA. Conclusions These results suggest that LINC00337 acts as an oncogenic lncRNA, targeting miR-1285-3p and regulating YTHDF1 expression, to promote the progression of lung adenocarcinoma.

scholarly journals Preclinical development of HQP1351, a multikinase inhibitor targeting a broad spectrum of mutant KIT kinases, for the treatment of imatinib-resistant gastrointestinal stromal tumors

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Xuechao Liu ◽  
Guangfeng Wang ◽  
Xianglei Yan ◽  
Haibo Qiu ◽  
Ping Min ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Clinical Trials ◽  
Cell Migration ◽  
Cell Lines ◽  
Gastrointestinal Stromal Tumors ◽  
Migration And Invasion ◽  
Stromal Tumors ◽  
Imatinib Resistant

Abstract Background Imatinib shows limited efficacy in patients with gastrointestinal stromal tumors (GISTs) carrying secondary KIT mutations. HQP1351, an orally bioavailable multikinase BCR-ABL inhibitor, is currently in clinical trials for the treatment of T315I mutant chronic myelogenous leukemia (CML), but the potential application in imatinib-resistant GISTs carrying secondary KIT mutations has not been explored. Methods The binding activities of HQP1351 with native or mutant KIT were first analyzed. Imatinib-sensitive GIST T1 and imatinib-resistant GIST 430 cells were employed to test the in vitro antiproliferative activity. Colony formation assay, cell migration assay and cell invasion assay were performed to evaluate the clonogenic, migration and invasion ability respectively. Flow cytometry and western blot analysis were used to detect cell apoptosis, cell cycle and signaling pathway. In vivo antitumor activity was evaluated in mouse xenograft models derived from GIST cell lines. Results HQP1351 potently inhibited both wild-type and mutant KIT kinases. In both imatinib-resistant and sensitive GIST cell lines, HQP1351 exhibited more potent or equivalent antiproliferative activity compared with ponatinib, a third generation BCR-ABL and KIT inhibitor. HQP1351 led to more profound inhibition of cell colony formation, cell migration and invasion, cell cycle arrest and cell apoptosis than ponatinib. Furthermore, HQP1351 also inhibited p-KIT, p-AKT, p-ERK1/2, and p-STAT3 to a higher extent than ponatinib. Finally, in xenograft tumor models derived from imatinib-resistant GIST cancer cell lines, HQP1351 exhibited antitumor activity superior to ponatinib. Conclusions Collectively, our in vitro and in vivo results suggest that the therapeutic application of HQP1351 in imatinib-resistant GIST patients deserves further investigation in clinical trials.

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