LGR5 regulates survival through mitochondria-mediated apoptosis and by targeting the Wnt/β-catenin signaling pathway in colorectal cancer cells

Hsu, Hung‐Chih; Liu, Yi-Shiuan; Tseng, Kai-Chi; Tan, Bertrand Chin‐Ming; Chen, Shu‐Jen; Chen, Hua‐Chien

doi:10.1016/j.cellsig.2014.07.004

Cited by 28 publications

(25 citation statements)

References 34 publications

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“…We showed that OPN overexpression in CRC correlated with higher grade, tumor stage, and survival of CRC patients, indicating that OPN overexpression was associated with poor prognosis. Stem-like nature of CRC cells has been suggested to associate with tumor progression, metastasis, and poor survival [ 16 , 17 ], which is in accordance with the clinicopathological characteristics observed in our patients with high OPN overexpression. In addition, OPN has been associated with cancer stem cell in colorectal cancer.…”

Section: Discussionsupporting

confidence: 89%

Osteopontin Overexpression Induced Tumor Progression and Chemoresistance to Oxaliplatin through Induction of Stem-Like Properties in Human Colorectal Cancer

Wan

Chow

et al. 2015

Stem Cells International

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Colorectal cancer (CRC) is one of the most common and fatal malignancies worldwide. The poor prognosis of colorectal cancer patients is due to development of chemoresistance and cancer metastasis. Recently osteopontin (OPN) has been associated with stem-like properties in colorectal cancer. This study further examined the clinicopathological significance of OPN in CRC and its effect on chemoresistance and transcription of stem cell markers. We examined the transcription level of OPN in 84 CRC patients and correlated the expression with their clinicopathological parameters. The associations of OPN overexpression with transcription of stem cell markers and response to chemotherapy in DLD1-OPN overexpressing clones and CRC patients were also investigated. Our results showed that OPN was significantly overexpressed in CRC, and its overexpression correlated with tumor stage and poor prognosis. Overexpression of CRC induced OCT4 and SOX2 expression in vitro and correlated with SOX2 overexpression in CRC patients. In addition, DLD1-OPN overexpressing cells showed enhanced ability to survive upon oxaliplatin treatment, and OPN expression was higher in CRC patients who were resistant to oxaliplatin-involved chemotherapy treatment. Thus, CRC cells overexpressing OPN demonstrated stem-like properties and OPN inhibition is a potential therapeutic approach to combat CRC progression and chemoresistance.

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Section: Discussionsupporting

confidence: 89%

Osteopontin Overexpression Induced Tumor Progression and Chemoresistance to Oxaliplatin through Induction of Stem-Like Properties in Human Colorectal Cancer

Wan

Chow

et al. 2015

Stem Cells International

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“…Multiple studies have proposed that LGR5 identifies tumour-initiating cells, or promotes ‘stemness' in colorectal cancer (CRC) ( Barker et al , 2009 ; Kemper et al , 2012 ; Kobayashi et al , 2012 ; Schepers et al , 2012 ; Hirsch et al , 2013 ). Further studies suggest a pro-survival role in CRC cells, thus raising the potential of LGR5 as a therapeutic target in CRC ( Al-Kharusi et al , 2013 ; Hirsch et al , 2013 ; Hsu et al , 2014 ). Nutrient deprivation occurs in a developing tumour when the metabolic demand exceeds that suppliable by the local vasculature ( Vaupel et al , 1989 ).…”

mentioning

confidence: 99%

Nutrient stress alters the glycosylation status of LGR5 resulting in reduced protein stability and membrane localisation in colorectal tumour cells: implications for targeting cancer stem cells

Morgan

Molnár

Collard³

et al. 2015

Br J Cancer

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Background:LGR5 is an important marker of intestinal stem cells and performs its vital functions at the cell membrane. Despite the importance of LGR5 to both normal and cancer stem cell biology, it is not known how microenvironmental stress affects the expression and subcellular distribution of the protein.Methods:Nutrient stress was induced through glucose starvation. Glycosylation status was assessed using endoglycosidase or tunicamycin treatment. Flow cytometry and confocal microscopy were used to assess subcellular distribution of LGR5.Results:Glucose deprivation altered the glycosylation status of LGR5 resulting in reduced protein stability and cell surface expression. Furthermore, inhibiting LGR5 glycosylation resulted in depleted surface expression and reduced localisation in the cis-Golgi network.Conclusions:Nutrient stress within a tumour microenvironment has the capacity to alter LGR5 protein stability and membrane localisation through modulation of LGR5 glycosylation status. As LGR5 surface localisation is required for enhanced Wnt signalling, this is the first report to show a mechanism by which the microenvironment could affect LGR5 function.

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“…Our previous studies revealed that LGR5 expression increased with the malignant degree of human gliomas, and knockdown of LGR5 was identified to lead to significant inhibition of the proliferation of glioma cells in vitro and in vivo (37). Additionally, Hsu et al (38) demonstrated that depletion of LGR5 induced apoptosis through the loss of mitochondrial membrane potential, and inhibited the activity of Wnt/β-catenin signaling by suppressing the expression of c-Myc and cyclin D in CRC cells (38). The western blotting results of the present study indicated that the expression of LGR5, pGSK-3β…”

Section: Discussionmentioning

confidence: 99%

MAP30 promotes apoptosis of U251 and U87 cells by suppressing the LGR5 and Wnt/β-catenin signaling pathway, and enhancing Smac expression

et al. 2018

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Abstract. Significant antitumor activity of Momordica anti-human immunodeficiency virus protein of 30 kDa (MAP30) purified from Momordica charantia has been the subject of previous research. However, the effective mechanism of MAP30 on malignant glioma cells has not yet been clarified. The aim of the present study was to investigate the effects and mechanism of MAP30 on U87 and U251 cell lines. A Cell Counting Kit-8 assay, wound healing assay and Transwell assay were used to detect the effects on U87 and U251 cells treated with different concentrations of MAP30 (0.5, 1, 2, 4, 8 and 16 µM) over different periods of time. Proliferation, migration and invasion of each cell line were markedly inhibited by MAP30 in a dose-and time-dependent manner. Flow cytometry and fluorescence staining demonstrated that apoptosis increased and the cell cycle was arrested in S-phase in the two investigated cell lines following MAP30 treatment. Western blot analysis demonstrated that leucine-rich-repeat-containing G-protein-coupled receptor 5 (LGR5) expression and key proteins in the Wnt/β-catenin signaling pathway were apparently decreased, whereas second mitochondria-derived activator of caspase (Smac) protein expression significantly increased with MAP30 treatment in the same manner. These results suggest that MAP30 markedly induces apoptosis in U87 and U251 cell lines by suppressing LGR5 and the Wnt/β-catenin signaling pathway, and enhancing Smac expression in a dose-and time-dependent manner.

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LGR5 regulates survival through mitochondria-mediated apoptosis and by targeting the Wnt/β-catenin signaling pathway in colorectal cancer cells

Cited by 28 publications

References 34 publications

Osteopontin Overexpression Induced Tumor Progression and Chemoresistance to Oxaliplatin through Induction of Stem-Like Properties in Human Colorectal Cancer

Osteopontin Overexpression Induced Tumor Progression and Chemoresistance to Oxaliplatin through Induction of Stem-Like Properties in Human Colorectal Cancer

Nutrient stress alters the glycosylation status of LGR5 resulting in reduced protein stability and membrane localisation in colorectal tumour cells: implications for targeting cancer stem cells

MAP30 promotes apoptosis of U251 and U87 cells by suppressing the LGR5 and Wnt/β-catenin signaling pathway, and enhancing Smac expression

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