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

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.

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

10.21203/rs.3.rs-41306/v1 ◽

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.

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Ginsenoside Rh1 inhibits colorectal cancer cell migration and invasion in vitro and tumor growth in vivo

Oncology Letters ◽

10.3892/ol.2019.10742 ◽

2019 ◽

Author(s):

Xi Lyu ◽

Xiaodong Xu ◽

Ailin Song ◽

Jinyi Guo ◽

Yawu Zhang ◽

...

Keyword(s):

Colorectal Cancer ◽

Cell Migration ◽

Tumor Growth ◽

Cancer Cell ◽

Colorectal Cancer Cell ◽

Migration And Invasion ◽

Cancer Cell Migration ◽

Cell Migration And Invasion

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Tripartite Motif Protein 6 Promotes Colorectal Cancer Cell Migration and Metastasis via SOCS2-STAT3 Signaling

Frontiers in Oncology ◽

10.3389/fonc.2021.695525 ◽

2021 ◽

Vol 11 ◽

Author(s):

Hongjian Zhao ◽

Junjun Huang ◽

Ming Chen ◽

Baoru Li ◽

Xinran Chen ◽

...

Keyword(s):

Colorectal Cancer ◽

Cell Migration ◽

Migration And Invasion ◽

Cytokine Signaling ◽

Cell Migration And Invasion ◽

Stat3 Phosphorylation ◽

Tripartite Motif ◽

Tripartite Motif Protein

Colorectal cancer (CRC) is one of the leading causes of cancer death worldwide, with most mortalities being caused by metastases. However, the underlying molecular mechanism of CRC metastases remains largely unknown. Emerging evidence has shown the role of the tripartite motif family, especially tripartite motif protein 6 (TRIM6), in carcinogenesis. In this study, we used CRC cell lines with TRIM6 knockdown and overexpression to investigate the function of TRIM6 in CRC metastasis. We found that TRIM6 promotes CRC cell migration and invasion both in vitro and in vivo. TRIM6 knockdown slows down the migration and invasion processes, whereas TRIM6 overexpression accelerates CRC cell migration and invasion. TRIM6 is potentially the upstream regulatory factor for signal transducer and activator of transcription 3 (STAT3) via the suppressor of cytokine signaling 2 (SOCS2). A total of 70 samples from patients with CRC further confirmed that TRIM6 expression level is positively correlated with STAT3 phosphorylation and negatively correlated with SOCS2 expression. Therefore, TRIM6 could be a potential therapeutic target for CRC metastasis.

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Pals1 prevents Rac1-dependent colorectal cancer cell metastasis by inhibiting Arf6

Molecular Cancer ◽

10.1186/s12943-021-01354-2 ◽

2021 ◽

Vol 20 (1) ◽

Author(s):

Simona Mareike Lüttgenau ◽

Christin Emming ◽

Thomas Wagner ◽

Julia Harms ◽

Justine Guske ◽

...

Keyword(s):

Colorectal Cancer ◽

Cell Migration ◽

Cancer Cells ◽

Cancer Cell ◽

Scaffolding Protein ◽

Migration And Invasion ◽

Tight Junction Formation ◽

Cell Metastasis ◽

Colorectal Cancer Cells

AbstractLoss of apical-basal polarity and downregulation of cell-cell contacts is a critical step during the pathogenesis of cancer. Both processes are regulated by the scaffolding protein Pals1, however, it is unclear whether the expression of Pals1 is affected in cancer cells and whether Pals1 is implicated in the pathogenesis of the disease.Using mRNA expression data and immunostainings of cancer specimen, we show that Pals1 is frequently downregulated in colorectal cancer, correlating with poorer survival of patients. We further found that Pals1 prevents cancer cell metastasis by controlling Rac1-dependent cell migration through inhibition of Arf6, which is independent of the canonical binding partners of Pals1. Loss of Pals1 in colorectal cancer cells results in increased Arf6 and Rac1 activity, enhanced cell migration and invasion in vitro and increased metastasis of transplanted tumor cells in mice. Thus, our data reveal a new function of Pals1 as a key inhibitor of cell migration and metastasis of colorectal cancer cells. Notably, this new function is independent of the known role of Pals1 in tight junction formation and apical-basal polarity.

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Resveratrol Enhances Inhibition Effects of Cisplatin on Cell Migration and Invasion and Tumor Growth in Breast Cancer MDA-MB-231 Cell Models In Vivo and In Vitro

Molecules ◽

10.3390/molecules26082204 ◽

2021 ◽

Vol 26 (8) ◽

pp. 2204

Author(s):

Meng-Die Yang ◽

Yang Sun ◽

Wen-Jun Zhou ◽

Xiao-Zheng Xie ◽

Qian-Mei Zhou ◽

...

Keyword(s):

Breast Cancer ◽

Cell Migration ◽

Tumor Growth ◽

Cell Viability ◽

Synergistic Effects ◽

Migration And Invasion ◽

Cell Migration And Invasion ◽

Tgf Β1

Triple-negative breast cancer (TNBC) is a refractory type of breast cancer that does not yet have clinically effective drugs. The aim of this study is to investigate the synergistic effects and mechanisms of resveratrol combined with cisplatin on human breast cancer MDA-MB-231 (MDA231) cell viability, migration, and invasion in vivo and in vitro. In vitro, MTS assays showed that resveratrol combined with cisplatin inhibits cell viability as a concentration-dependent manner, and produced synergistic effects (CI < 1). Transwell assay showed that the combined treatment inhibits TGF-β1-induced cell migration and invasion. Immunofluorescence assays confirmed that resveratrol upregulated E-cadherin expression and downregulated vimentin expression. Western blot assay demonstrated that resveratrol combined with cisplatin significantly reduced the expression of fibronectin, vimentin, P-AKT, P-PI3K, P-JNK, P-ERK, Sma2, and Smad3 induced by TGF-β1 (p < 0.05), and increased the expression of E-cadherin (p < 0.05), respectively. In vivo, resveratrol enhanced tumor growth inhibition and reduced body weight loss and kidney function impairment by cisplatin in MDA231 xenografts, and significantly reduced the expressions of P-AKT, P-PI3K, Smad2, Smad3, P-JNK, P-ERK, and NF-κB in tumor tissues (p < 0.05). These results indicated that resveratrol combined with cisplatin inhibits the viability of breast cancer MDA231 cells synergistically, and inhibits MDA231 cells invasion and migration through Epithelial-mesenchymal transition (EMT) approach, and resveratrol enhanced anti-tumor effect and reduced side of cisplatin in MDA231 xenografts. The mechanism may be involved in the regulations of PI3K/AKT, JNK, ERK and NF-κB expressions.

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2, 3-Dihydro-3β-methoxy Withaferin-A Lacks Anti-Metastasis Potency: Bioinformatics and Experimental Evidences

Scientific Reports ◽

10.1038/s41598-019-53568-6 ◽

2019 ◽

Vol 9 (1) ◽

Cited By ~ 2

Author(s):

Anupama Chaudhary ◽

Rajkumar S. Kalra ◽

Vidhi Malik ◽

Shashank P. Katiyar ◽

Durai Sundar ◽

...

Keyword(s):

Cell Migration ◽

Cancer Cells ◽

Cancer Cell ◽

Human Cancer ◽

Effector Proteins ◽

Withaferin A ◽

Migration And Invasion ◽

Cell Metastasis

AbstractWithaferin-A is a withanolide, predominantly present in Ashwagandha (Withania somnifera). It has been shown to possess anticancer activity in a variety of human cancer cells in vitro and in vivo. Molecular mechanism of such cytotoxicity has not yet been completely understood. Withaferin-A and Withanone were earlier shown to activate p53 tumor suppressor and oxidative stress pathways in cancer cells. 2,3-dihydro-3β-methoxy analogue of Withaferin-A (3βmWi-A) was shown to lack cytotoxicity and well tolerated at higher concentrations. It, on the other hand, protected normal cells against oxidative, chemical and UV stresses through induction of anti-stress and pro-survival signaling. We, in the present study, investigated the effect of Wi-A and 3βmWi-A on cell migration and metastasis signaling. Whereas Wi-A binds to vimentin and heterogeneous nuclear ribonucleoprotein K (hnRNP-K) with high efficacy and downregulates its effector proteins, MMPs and VEGF, involved in cancer cell metastasis, 3βmWi-A was ineffective. Consistently, Wi-A, and not 3βmWi-A, caused reduction in cytoskeleton proteins (Vimentin, N-Cadherin) and active protease (u-PA) that are essential for three key steps of cancer cell metastasis (EMT, increase in cell migration and invasion).

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Acyl-CoA Synthetase 5 Promotes the Growth and Invasion of Colorectal Cancer Cells

Canadian Journal of Gastroenterology and Hepatology ◽

10.1155/2017/7615736 ◽

2017 ◽

Vol 2017 ◽

pp. 1-14 ◽

Cited By ~ 3

Author(s):

Shihua Ding ◽

Shaohui Tang ◽

Min Wang ◽

Donghai Wu ◽

Haijian Guo

Keyword(s):

Colorectal Cancer ◽

Cell Proliferation ◽

Cell Migration ◽

Cell Apoptosis ◽

Migration And Invasion ◽

Cell Migration And Invasion ◽

Sw620 Cells ◽

Role Of It

Background and Aims. Acyl-CoA synthetase 5 (ACS5) has been reported to be associated with the development of various cancers, but the role of it in colorectal cancer (CRC) is not well understood. The present study aimed to explore the potential role of ACS5 in the development and progression of CRC. Methods. ACS5 expression in CRC tissues and CRC cell lines was examined, and its clinical significance was analyzed. The role of ACS5 in cell proliferation, apoptosis, and invasion was examined in vitro. Results. We found that ACS5 expression was upregulated in CRC cells and CRC tissues and that high ACS5 expression was more frequent in CRC patients with excess muscular layer and with poor tumor differentiation. Furthermore, knockdown of ACS5 in HT29 and SW480 cells significantly dampened cell proliferation, induced cell apoptosis, and reduced cell migration and invasion. In contrast, the ectopic overexpression of ACS5 in LOVO and SW620 cells remarkably promoted cell proliferation, inhibited cell apoptosis, and enhanced cell migration and invasion. Enhanced cell growth and invasion ability mediated by the gain of ACS5 expression were associated with downregulation of caspase-3 and E-cadherin and upregulation of survivin and CD44. Conclusions. Our data demonstrate that ACS5 can promote the growth and invasion of CRC cells and provide a potential target for CRC gene therapy.

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A high-throughput 3D bioprinted cancer cell migration and invasion model with versatile and broad biological applicability

10.1101/2021.12.28.474387 ◽

2021 ◽

Author(s):

MoonSun Jung ◽

Joanna Skhinas ◽

Eric Y Du ◽

Maria Kristine Tolentino ◽

Robert Utama ◽

...

Keyword(s):

Cell Migration ◽

High Throughput ◽

Drug Screening ◽

Cancer Biology ◽

Cell Movement ◽

Migration And Invasion ◽

Cell Migration And Invasion ◽

Drop On Demand

Understanding the underlying mechanisms of migration and metastasis is a key focus of cancer research. There is an urgent need to develop in vitro 3D tumor models that can mimic physiological cell-cell and cell-extracellular matrix interactions, with high reproducibility and that are suitable for high throughput (HTP) drug screening. Here, we developed a HTP 3D bioprinted migration model using a bespoke drop-on-demand bioprinting platform. This HTP platform coupled with tunable hydrogel systems enables (i) the rapid encapsulation of cancer cells within in vivo tumor mimicking matrices, (ii) in situ and real-time measurement of cell movement, (iii) detailed molecular analysis for the study of mechanisms underlying cell migration and invasion, and (iv) the identification of novel therapeutic options. This work demonstrates that this HTP 3D bioprinted cell migration platform has broad applications across quantitative cell and cancer biology as well as drug screening.

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