scholarly journals Rapamycin Inhibits ALDH Activity, Resistance to Oxidative Stress, and Metastatic Potential in Murine Osteosarcoma Cells

Sarcoma ◽  
2013 ◽  
Vol 2013 ◽  
pp. 1-11 ◽  
Author(s):  
Xiaodong Mu ◽  
Christian Isaac ◽  
Trevor Schott ◽  
Johnny Huard ◽  
Kurt Weiss
Keyword(s):  
Oxidative Stress ◽  
Experimental System ◽  
Metastatic Potential ◽  
Bone Morphogenetic Protein 2 ◽  
Stem Cell Marker ◽  
Migration And Invasion ◽  
Aldh Activity ◽  
Primary Malignancy ◽  
Rapamycin Treatment

Osteosarcoma (OS) is the most common primary malignancy of bone. Mortality is determined by the presence of metastatic disease, but little is known regarding the biochemical events that drive metastases. Two murine OS cell lines, K7M2 and K12, are related but differ significantly in their metastatic potentials: K7M2 is highly metastatic whereas K12 displays much less metastatic potential. Using this experimental system, the mammalian target of rapamycin (mTOR) pathway has been implicated in OS metastasis. We also discovered that aldehyde dehydrogenase (ALDH, a stem cell marker) activity is higher in K7M2 cells than K12 cells. Rapamycin treatment reduces the expression and enzymatic activity of ALDH in K7M2 cells. ALDH inhibition renders these cells more susceptible to apoptotic death when exposed to oxidative stress. Furthermore, rapamycin treatment reduces bone morphogenetic protein-2 (BMP2) and vascular endothelial growth factor (VEGF) gene expression and inhibits K7M2 proliferation, migration, and invasionin vitro. Inhibition of ALDH with disulfiram correlated with decreased mTOR expression and activity. In conclusion, we provide evidence for interaction between mTOR activity, ALDH activity, and metastatic potential in murine OS cells. Our work suggests that mTOR and ALDH are therapeutic targets for the treatment and prevention of OS metastasis.

scholarly journals Aldehyde Dehydrogenases: Not Just Markers, but Functional Regulators of Stem Cells

2019 ◽  
Vol 2019 ◽  
pp. 1-15 ◽  
Author(s):  
Giuseppe Vassalli
Keyword(s):  
Stem Cells ◽  
Molecular Mechanisms ◽  
Cell Types ◽  
Cellular Function ◽  
Stem Cell Marker ◽  
Cell Populations ◽  
Aldh Activity ◽  
Cellular Functions ◽  
Stem And Progenitor Cells

Aldehyde dehydrogenase (ALDH) is a superfamily of enzymes that detoxify a variety of endogenous and exogenous aldehydes and are required for the biosynthesis of retinoic acid (RA) and other molecular regulators of cellular function. Over the past decade, high ALDH activity has been increasingly used as a selectable marker for normal cell populations enriched in stem and progenitor cells, as well as for cell populations from cancer tissues enriched in tumor-initiating stem-like cells. Mounting evidence suggests that ALDH not only may be used as a marker for stem cells but also may well regulate cellular functions related to self-renewal, expansion, differentiation, and resistance to drugs and radiation. ALDH exerts its functional actions partly through RA biosynthesis, as all-trans RA reverses the functional effects of pharmacological inhibition or genetic suppression of ALDH activity in many cell types in vitro. There is substantial evidence to suggest that the role of ALDH as a stem cell marker comes down to the specific isoform(s) expressed in a particular tissue. Much emphasis has been placed on the ALDH1A1 and ALDH1A3 members of the ALDH1 family of cytosolic enzymes required for RA biosynthesis. ALDH1A1 and ALDH1A3 regulate cellular function in both normal stem cells and tumor-initiating stem-like cells, promoting tumor growth and resistance to drugs and radiation. An improved understanding of the molecular mechanisms by which ALDH regulates cellular function will likely open new avenues in many fields, especially in tissue regeneration and oncology.

scholarly journals ATM regulation of IL-8 links oxidative stress to cancer cell migration and invasion

eLife ◽  
2015 ◽  
Vol 4 ◽  
Author(s):  
Wei-Ta Chen ◽  
Nancy D Ebelt ◽  
Travis H Stracker ◽  
Blerta Xhemalce ◽  
Carla L Van Den Berg ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Cell Migration ◽  
Cancer Cells ◽  
Metastatic Cancer ◽  
Xenograft Model ◽  
Metastatic Potential ◽  
Migration And Invasion ◽  
Cell Migration And Invasion ◽  
Mouse Xenograft Model ◽  
Cancer Suppression

Ataxia-telangiectasia mutated (ATM) protein kinase regulates the DNA damage response (DDR) and is associated with cancer suppression. Here we report a cancer-promoting role for ATM. ATM depletion in metastatic cancer cells reduced cell migration and invasion. Transcription analyses identified a gene network, including the chemokine IL-8, regulated by ATM. IL-8 expression required ATM and was regulated by oxidative stress. IL-8 was validated as an ATM target by its ability to rescue cell migration and invasion defects in ATM-depleted cells. Finally, ATM-depletion in human breast cancer cells reduced lung tumors in a mouse xenograft model and clinical data validated IL-8 in lung metastasis. These findings provide insights into how ATM activation by oxidative stress regulates IL-8 to sustain cell migration and invasion in cancer cells to promote metastatic potential. Thus, in addition to well-established roles in tumor suppression, these findings identify a role for ATM in tumor progression.

scholarly journals Overexpression of Mitochondrial IF1 Prevents Metastatic Disease of Colorectal Cancer by Enhancing Anoikis and Tumor Infiltration of NK Cells

Cancers ◽  
2019 ◽  
Vol 12 (1) ◽  
pp. 22 ◽  
Author(s):  
Lucía González-Llorente ◽  
Fulvio Santacatterina ◽  
Ana García-Aguilar ◽  
Cristina Nuevo-Tapioles ◽  
Sara González-García ◽  
...  
Keyword(s):  
Nk Cells ◽  
Cancer Progression ◽  
Immune Surveillance ◽  
Metastatic Potential ◽  
Disease Recurrence ◽  
Metabolic Reprogramming ◽  
Migration And Invasion ◽  
Tumorigenic Potential

Increasing evidences show that the ATPase Inhibitory Factor 1 (IF1), the physiological inhibitor of the ATP synthase, is overexpressed in a large number of carcinomas contributing to metabolic reprogramming and cancer progression. Herein, we show that in contrast to the findings in other carcinomas, the overexpression of IF1 in a cohort of colorectal carcinomas (CRC) predicts less chances of disease recurrence, IF1 being an independent predictor of survival. Bioinformatic and gene expression analyses of the transcriptome of colon cancer cells with differential expression of IF1 indicate that cells overexpressing IF1 display a less aggressive behavior than IF1 silenced (shIF1) cells. Proteomic and functional in vitro migration and invasion assays confirmed the higher tumorigenic potential of shIF1 cells. Moreover, shIF1 cells have increased in vivo metastatic potential. The higher metastatic potential of shIF1 cells relies on increased cFLIP-mediated resistance to undergo anoikis after cell detachment. Furthermore, tumor spheroids of shIF1 cells have an increased ability to escape from immune surveillance by NK cells. Altogether, the results reveal that the overexpression of IF1 acts as a tumor suppressor in CRC with an important anti-metastatic role, thus supporting IF1 as a potential therapeutic target in CRC.

scholarly journals Knockdown of 91 H Suppresses the Tumorigenesis of Osteosarcoma via Inducing Methylation of CDK4 Promoter

2021 ◽  
Vol 20 ◽  
pp. 153303382199000
Author(s):  
Suoli Cheng ◽  
Jianping Zheng ◽  
Xueqin Liu ◽  
Jiandang Shi ◽  
Fan Gong ◽  
...  
Keyword(s):  
Cell Apoptosis ◽  
Migration And Invasion ◽  
G1 Arrest ◽  
Osteosarcoma Cells ◽  
Mice Model ◽  
Primary Malignancy ◽  
Specific Pcr ◽  
Xenograft Mice Model

Background: Osteosarcoma is the most leading primary malignancy of the bone in adolescents all over the world. Long non-coding RNA (lncRNA) 91 H has been reported to participated in multiple cancers. Meanwhile, lncRNA 91 H has been proved to be upregulated in osteosarcoma. However, the function of 91 H in osteosarcoma remains unclear. Methods: Gene and protein expressions in osteosarcoma cells were detected by qRT-PCR and western blot, respectively. Cell viability was tested by CCK-8 assay. Ki67 staining was used to measure cell proliferation. Cell apoptosis and cycle were assessed by flow cytometry. In addition, transwell assay was used to detect cell migration and invasion. Furthermore, Methylation-specific PCR (MSP) was performed to test the methylation of CDK4 promoter. Finally, xenograft mice model was established to explore the role of 91 H in osteosarcoma in vivo. Results: Knockdown of 91 H significantly inhibited the growth of osteosarcoma cells via inducing the cell apoptosis. In addition, 91 H siRNA notably suppressed the migration and invasion of osteosarcoma cells. Meanwhile, knockdown of 91 H inhibited the progression of osteosarcoma via inducing methylation of CDK4 promoter. Furthermore, 91 H knockdown obviously induced G1 arrest in osteosarcoma cells via inhibition of PCNA and Cyclin D1. Finally, knockdown of 91 H notably inhibited the tumor growth of osteosarcoma in vivo. Conclusion: knockdown of 91 H suppressed the tumorigenesis of osteosarcoma via inducing methylation of CDK4 promoter in vitro and in vivo. Thus, 91 H may serve as a new target for the treatment of osteosarcoma.

scholarly journals Alpha Ketoglutarate Exerts In Vitro Anti-Osteosarcoma Effects through Inhibition of Cell Proliferation, Induction of Apoptosis via the JNK and Caspase 9-Dependent Mechanism, and Suppression of TGF-β and VEGF Production and Metastatic Potential of Cells

2020 ◽  
Vol 21 (24) ◽  
pp. 9406
Author(s):  
Katarzyna Kaławaj ◽  
Adrianna Sławińska-Brych ◽  
Magdalena Mizerska-Kowalska ◽  
Aleksandra Żurek ◽  
Agnieszka Bojarska-Junak ◽  
...  
Keyword(s):  
Growth Factor ◽  
Cell Lines ◽  
Specific Inhibitor ◽  
Metastatic Potential ◽  
Migration And Invasion ◽  
Osteosarcoma Cell ◽  
Dependent Manner ◽  
Caspase 9 ◽  
Anti Cancer

Osteosarcoma (OS) is the most common type of primary bone tumor. Currently, there are limited treatment options for metastatic OS. Alpha-ketoglutarate (AKG), i.e., a multifunctional intermediate of the Krebs cycle, is one of the central metabolic regulators of tumor fate and plays an important role in cancerogenesis and tumor progression. There is growing evidence suggesting that AKG may represent a novel adjuvant therapeutic opportunity in anti-cancer therapy. The present study was intended to check whether supplementation of Saos-2 and HOS osteosarcoma cell lines (harboring a TP53 mutation) with exogenous AKG exerted an anti-cancer effect. The results revealed that AKG inhibited the proliferation of both OS cell lines in a concentration-dependent manner. As evidenced by flow cytometry, AKG blocked cell cycle progression at the G1 stage in both cell lines, which was accompanied by a decreased level of cyclin D1 in HOS and increased expression of p21Waf1/Cip1 protein in Saos-2 cells (evaluated with the ELISA method). Moreover, AKG induced apoptotic cell death and caspase-3 activation in both OS cell lines (determined by cytometric analysis). Both the immunoblotting and cytometric analysis revealed that the AKG-induced apoptosis proceeded predominantly through activation of an intrinsic caspase 9-dependent apoptotic pathway and an increased Bax/Bcl-2 ratio. The apoptotic process in the AKG-treated cells was mediated via c-Jun N-terminal protein kinase (JNK) activation, as the specific inhibitor of this kinase partially rescued the cells from apoptotic death. In addition, the AKG treatment led to reduced activation of extracellular signal-regulated kinase (ERK1/2) and significant inhibition of cell migration and invasion in vitro concomitantly with decreased production of pro-metastatic transforming growth factor β (TGF-β) and pro-angiogenic vascular endothelial growth factor (VEGF) in both OS cell lines suggesting the anti-metastatic potential of this compound. In conclusion, we showed the anti-osteosarcoma potential of AKG and provided a rationale for a further study of the possible application of AKG in OS therapy.

scholarly journals Expression of Potential Cancer Stem Cell Marker ABCG2 is Associated with Malignant Behaviors of Hepatocellular Carcinoma

2013 ◽  
Vol 2013 ◽  
pp. 1-12 ◽  
Author(s):  
Guang Zhang ◽  
Zhongxia Wang ◽  
Weihuan Luo ◽  
Hongbo Jiao ◽  
Junhua Wu ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Stem Cells ◽  
Drug Resistance ◽  
Cancer Stem Cells ◽  
Expression Level ◽  
Stem Cell Marker ◽  
Migration And Invasion ◽  
Close Relationship ◽  
A Minor

Background. Despite improvement in treatment, the prognosis of hepatocellular carcinoma (HCC) remains disastrous. Cancer stem cells (CSCs) may be responsible for cancer malignant behaviors. ATP-binding cassette, subfamily G, member 2 (ABCG2) is widely expressed in both normal and cancer stem cells and may play an important role in cancer malignant behaviors.Methods. The expression of ABCG2 in HCC tissues and SMMC-7721 cells was examined, and the relevance of ABCG2 expression with clinical characteristics was analyzed. ABCG2+ and ABCG2− cells were sorted, and the potential of tumorigenicity was determined. Expression level of ABCG2 was manipulated by RNA interference and overexpression. Malignant behaviors including proliferation, drug resistance, migration, and invasion were studied in vitro.Results. Expression of ABCG2 was found in a minor group of cells in HCC tissues and cell lines. ABCG2 expression showed tendencies of association with unfavorable prognosis factors. ABCG2 positive cells showed a superior tumorigenicity. Upregulation of ABCG2 enhanced the capacity of proliferation, doxorubicin resistance, migration, and invasion potential, while downregulation of ABCG2 significantly decreased these malignant behaviors.Conclusion. Our results indicate that ABCG2 is a potential CSC marker for HCC. Its expression level has a close relationship with tumorigenicity, proliferation, drug resistance, and metastasis ability.

Antimigratory and antimetastatic effect of heparin-derived 4–18 unit oligosaccharides in a preclinical human melanoma metastasis model

2009 ◽  
Vol 102 (12) ◽  
pp. 1265-1273 ◽  
Author(s):  
István Kenessey ◽  
Erika Simon ◽  
Krisztina Futosi ◽  
Bíborka Bereczky ◽  
Andrea Kiss ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Cell Migration ◽  
Metastatic Potential ◽  
Inhibitory Effect ◽  
Human Melanoma ◽  
Migration And Invasion ◽  
Melanoma Metastasis ◽  
Metastasis Model

SummaryHeparin and its derivatives have been shown to inhibit angiogenesis and metastasis formation. Accordingly, we investigated the effect of heparin fragments containing 4 to 22 monomers on human melanoma cell proliferation, migration and invasion in vitro as well as on the in vivo metastatic potential in a SCID mouse model. Only oligosaccharide dp18 had significant inhibitory effect on cell proliferation. In contrast, cell migration was inhibited by all oligosaccharides studied except dp8 and dp22. Anti CD44v3 antibody stimulated cell migration and invasion, and this effect could be attenuated by oligosaccharides dp4 and dp18. These fragments also inhibited the catalytic activity of myosin light chain phosphatase as well. Moreover, oligosaccharides dp4 and dp18 reduced the number of lung colonies formed in SCID mice intravenously injected with human melanoma cells, while dp22 proved to be ineffective in this respect.These studies revealed that fragments of heparin have an antimigratory and antimetastatic potential. These fragments lack the haemostatic effect of heparin, suggesting that they are potential specific antimetastatic agents in anticancer therapy.

scholarly journals MnTnHex-2-PyP5+, Coupled to Radiation, Suppresses Metastasis of 4T1 and MDA-MB-231 Breast Cancer via AKT/Snail/EMT Pathways

Antioxidants ◽  
2021 ◽  
Vol 10 (11) ◽  
pp. 1769
Author(s):  
Sung-Won Shin ◽  
Changhoon Choi ◽  
Hakyoung Kim ◽  
Yeeun Kim ◽  
Sohee Park ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast ◽  
Metastatic Potential ◽  
Migration And Invasion ◽  
Tumor Growth Inhibition ◽  
Snail Expression ◽  
Mesenchymal Transition ◽  
4T1 Cells

Tumor migration and invasion induced by the epithelial-to-mesenchymal transition (EMT) are prerequisites for metastasis. Here, we investigated the inhibitory effect of a mimic of superoxide dismutase (SOD), cationic Mn(III) ortho-substituted N-n-hexylpyridylporphyrin (MnTnHex-2-PyP5+, MnHex) on the metastasis of breast cancer in cellular and animal models, focusing on the migration of tumor cells and the factors that modulate this behavior. Wound healing and Transwell migration assays revealed that the migration of mouse mammary carcinoma 4T1 cells was markedly reduced during the concurrent treatment of MnHex and radiation therapy (RT) compared with that of the control and RT alone. Bioluminescence imaging showed that MnHex/RT co-treatment dramatically reduced lung metastasis of 4T1 cells in mice, compared with the sham control and both single treatments. Western blotting and immunofluorescence showed that MnHex treatment of 4T1 cells reversed the RT-induced EMT via inhibiting AKT/GSK-3β/Snail pathway in vitro, thereby decreasing cell migration and invasion. Consistently, histopathological analyses of 4T1 tumors showed that MnHex/RT reduced Snail expression, blocked EMT, and in turn suppressed metastases. Again, in the human metastatic breast cancer MDA-MB-231 cell line, MnHex inhibited metastatic potential in vitro and in vivo and suppressed the RT-induced Snail expression. In addition to our previous studies showing tumor growth inhibition, this study demonstrated that MnHex carries the ability to minimize the metastatic potential of RT-treated cancers, thus overcoming their radioresistance.

scholarly journals CXCL14 facilitates the growth and metastasis of ovarian carcinoma cells via activation of the Wnt/β-catenin signaling pathway

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Li-Na Gao ◽  
Man Hao ◽  
Xiao-Hui Liu ◽  
Li Zhang ◽  
Yan Dong ◽  
...  
Keyword(s):  
Cell Growth ◽  
Signaling Pathway ◽  
Molecular Mechanisms ◽  
Epithelial Mesenchymal Transition ◽  
Mrna Level ◽  
Metastatic Potential ◽  
Migration And Invasion ◽  
Migration Ability ◽  
Mesenchymal Transition

Abstract Background There is an urgent need to identify potential targets in anticancer therapy to improve the survival and prognosis of patients with ovarian cancer (OC). Herein, we investigated the functional significance of chemokine (C-X-C motif) ligand 14 (CXCL14) in OC cell growth and epithelial–mesenchymal transition (EMT). Methods qRT PCR and western blotting was used to detect CXCL14 mRNA level and protein expression, respectively. The functional mechanism of CXCL14 in OC was investigated by CCK-8, colony formation and transwell assays. The migration ability of OC cell was determined using wound healing. The protein expressions of CXCL14 and β-catenin in OC tissues were determined by immumohistochemical staining. Results We demonstrated that high levels of CXCL14 were associated with a worse prognosis in patients with OC. CXCL14 knockdown considerably restrained the growth, migration and invasion of OC cell in vitro. In contrast, ectopic CXCL14 overexpression yielded the opposite results. Investigations to determine the underlying molecular mechanisms revealed that the Wnt/β-catenin signaling pathway is involved in CXCL14-facilitated OC cell invasiveness. Conclusion These data collectively demonstrate that CXCL14 contributes to OC cell growth and metastatic potential by regulating the Wnt/β-catenin signaling pathway.

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