Suppression of renal cell carcinoma growth by inhibition of Notch signaling in vitro and in vivo

Sjölund, Jonas; Johansson, Martin; Manna, Sukumar; Norin, Carl; Pietras, Alexander; Beckman, Siv; Nilsson, Elise; Ljungberg, Börje; Axelson, Håkan

doi:10.1172/jci32086

Cited by 159 publications

(155 citation statements)

References 66 publications

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“…Our group and other investigators have reported the critical role played by the oncogenic PI3K/Akt, NF-kB and MAPK signaling pathways as well as by the developmental Notch and SHH-Gli signaling in human CCC tumorigenesis (Sourbier et al, 2006Huang et al, 2008;Sjolund et al, 2008;Dormoy et al, 2009). In all cases, these pathways were shown to be constitutively activated and turned towards tumor growth regardless of VHL status.…”

Section: Discussionmentioning

confidence: 68%

“…In that context, the idea that tumors hijack signaling pathways and molecular factors/markers involved in normal development for their own growth has recently taken hold of investigators. Consequently, Sjolund et al (2008) and Hueber et al (2006Hueber et al ( , 2008 have shown that the developmental Notch signaling cascade and Pax2, critical for nephrogenesis, are constitutively active in human CCC cell lines and have growth-promoting effect. More recently, we have reached similar conclusions concerning the involvement of the developmental sonic hedgehog (SHH) signaling pathway in human CCC progression, and we showed further that the SHH signaling pathway has orchestral roles in the activation of oncogenic pathways in this disease, including the phosphoinositide kinase-3 (PI3K)/ Akt, the nuclear factor-kappaB (NF-kB) and mitogenactivated protein kinase (MAPK) signaling pathways (Dormoy et al, 2009).…”

Section: Introductionmentioning

confidence: 99%

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LIM-class homeobox gene Lim1, a novel oncogene in human renal cell carcinoma

et al. 2010

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Section: Discussionmentioning

confidence: 68%

Section: Introductionmentioning

confidence: 99%

LIM-class homeobox gene Lim1, a novel oncogene in human renal cell carcinoma

et al. 2010

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“…All these results demonstrate the versatile role of KLF4 in Twist1-induced endothelial differentiation, stem-like property and metastasis. The knowledge gained from this report has therapeutic implications for combining g-secretase inhibitors 32 with other chemotherapeutic agents to achieve additive tumour-killing effects in Twist1-overexpressing tumours, especially in head and neck tumours with a percentage (35-45%) expressing Twist1 11,24 .…”

Section: Oecm1-twist1mentioning

confidence: 91%

“…Jagged1 promoter (with E-box) Jagged1 promoter (without E-box) (DAPT) that inhibits Notch signalling 32 . Overexpression of Twist1 increased the viability of cells treated with either cetuximab or cisplatin that could be abolished by KLF4 knockdown ( Supplementary Fig.…”

Section: Oecm1-twist1mentioning

confidence: 99%

Twist1 induces endothelial differentiation of tumour cells through the Jagged1-KLF4 axis

et al. 2014

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The mechanisms controlling tumour-induced angiogenesis are presently not clear. In principle, angiogenesis can be achieved through the activation of endothelial cells in existing vessels or by transdifferentiation of tumour cells into endothelial cells. However, whether tumour cells can go through a prior epithelial-mesenchymal transition and further differentiate into endothelial cells remains unknown. Here we show that overexpression of Twist1, a transcriptional regulator that induces and promotes cancer metastasis, leads to endothelial differentiation in head and neck cancer (HNC) cells. Induction of Jagged1 expression by Twist1 is essential for Twist1-induced endothelial differentiation. The Jagged1/ Notch signalling subsequently activates KLF4, inducing stem-like properties in HNC cells and conferring them with drug resistance. Our results indicate that the Twist1-Jagged1/KLF4 axis is essential both for transdifferentiation of tumour cells into endothelial cells and for chemoresistance acquisition.

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“…Treatment with γ-secretase inhibitor, DAPT (N-[N-(3,5-difluorophenacetyl)-L-alanyl]-S-phenylglycine t-butyl ester) resulted in a marked reduction in medulloblastoma growth and induced G0-G1 cell cycle arrest and apoptosis in a T-ALL mouse model [17] . And DAPT have been shown to inhibit renal cell carcinoma growth in vitro and in vivo and inhibit the growth of pancreatic cancer cells in vitro by inhibition of Notch signaling [18,19] .…”

Section: Introductionmentioning

confidence: 99%

γ-Secretase inhibitor, DAPT inhibits self-renewal and stemness maintenance of ovarian cancer stem-like cells in vitro

Jiang

Zhang

et al. 2011

Chin. J. Cancer Res.

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Objective: The Notch signaling pathway plays an important role in the stem cell signaling network and contributes to tumorigenesis. However, the functions of Notch signaling in ovarian cancer stem cells (OCSCs) are not well understood. We aimed to investigate the effects of Notch blockade on self-renewal and stemness maintenance of OCSCs.Methods: Ovarian cancer stem-like cells were enriched from ovarian cancer cell lines in serum-free medium. A γ-secretase inhibitor, (DAPT), was used to block Notch signaling. MTT assays were performed to assess self-renewal and proliferation inhibition, flow cytometry was performed to analyze cell surface marker and immunofluorescence, Western Blot and Real-time RT-PCR assays were performed to detect Oct4 and Sox2 protein and mRNA expression of the Ovarian cancer stem-like cells treated with DAPT.Results: Notch blockade markedly inhibits self-renewal and proliferation of ovarian cancer stem-like cells, significantly downregulates the expression of OCSCs-specific surface markers, and reduces protein and mRNA expression of Oct4 and Sox2 in OCSC-like cells.Conclusion: Our results suggest that Notch signaling is not only critical for the self-renewal and proliferation of OCSCs, but also for the stemness maintenance of OCSCs. The γ-secretase inhibitor is a promising treatment targeting OCSCs.

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Suppression of renal cell carcinoma growth by inhibition of Notch signaling in vitro and in vivo

Cited by 159 publications

References 66 publications

LIM-class homeobox gene Lim1, a novel oncogene in human renal cell carcinoma

LIM-class homeobox gene Lim1, a novel oncogene in human renal cell carcinoma

Twist1 induces endothelial differentiation of tumour cells through the Jagged1-KLF4 axis

γ-Secretase inhibitor, DAPT inhibits self-renewal and stemness maintenance of ovarian cancer stem-like cells in vitro

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