Modulation of post-translational modifications in β-catenin and LRP6 inhibits Wnt signaling pathway in pancreatic cancer

Garg, Bharti; Giri, Bhuwan; Majumder, Kaustav; Dudeja, Vikas; Banerjee, Sulagna; Saluja, Ashok K.

doi:10.1016/j.canlet.2016.11.026

Cited by 44 publications

(36 citation statements)

References 36 publications

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“…The inhibition of LRP-6 phosphorylation downregulates Wnt/β-catenin signaling. For example, triptolide, a diterpene epoxide derived from a natural product, inhibits LRP-6 phosphorylation and pancreatic cancer proliferation in a mouse model (KPC (Kras G12D , P53 R172H PDX Cre ) of pancreatic-derived tumors [52]. In this study, RP-010 significantly downregulated LRP-6 expression.…”

Section: Discussionmentioning

confidence: 58%

The Novel Thienopyrimidine Derivative, RP-010, Produces Its Efficacy in Prostate Cancer Cells by Inducing the Fragmentation of β-catenin

Amawi¹,

Hussein²,

Boddu³

et al. 2019

Preprint

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Thienopyrimidines are a versatile group of compounds that contain a biologically active pharmacophore and reported to have anticancer efficacy in vitro. Here, we report for the first time, that thieno[3,2-d]pyrimidine - based compounds, designated the RP series, have efficacy in prostate cancer cells. The lead compound, RP-010, was efficacious in PC3 and DU-145 prostate cancer (PC) cells (IC50< 1µM). The cytotoxicity of RP-010 was significantly lower in normal cells. RP-010 (0.5, 1, 2, and 4 µM) arrested prostate cancer cells in the G2 phase of the cell cycle, induced mitotic catastrophe and apoptotic signaling in both PC cell lines. Mechanistic studies suggested that RP-010 (1 and 2 µM) inhibits the wingless-type MMTV (Wnt)/β-catenin signaling pathway, mainly by inducing β-catenin fragmentation, while down regulating important proteins in the pathway, i.e. LRP-6, DVL3, and c-Myc. Interestingly, RP-010 (1 and 2 µM) induced the nuclear translocation of the negative feedback proteins, Naked 1 and Naked 2, in the signaling pathway. In addition, RP-010 (0.5, 1, 2, and 4 µM) significantly decreased the migration and invasiveness of PC cells in vitro. Finally, RP-010 did not produce significant toxic effects in zebrafish at concentrations up to 6 µM. In conclusion, RP-10 is a promising anticancer compound in metastatic prostate cancer and did not produce overt toxicity in an in vivo zebrafish model. Future mechanistic and efficacy studies are needed in-vivo to optimize the lead compound RP-010 for clinical use.

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Section: Discussionmentioning

confidence: 58%

The Novel Thienopyrimidine Derivative, RP-010, Produces Its Efficacy in Prostate Cancer Cells by Inducing the Fragmentation of β-catenin

Amawi¹,

Hussein²,

Boddu³

et al. 2019

Preprint

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“…Studies from our laboratory have shown that O-GlcNAc modification of Sp1 regulates its nuclear translocation and thus its activity (5). We have also shown that O-GlcNAc modification of β-catenin in pancreatic cancer regulates the Wnt signaling pathway (15). In the current study, we have evaluated the role of O-GlcNAc modification on SOX2, the key transcription factor regulating self-renewal in cancer cells.…”

Section: Cancer Cells Undergo Drastic Metabolic Reprogramming That Nomentioning

confidence: 85%

O-GlcNAc modification of oncogenic transcription factor Sox2 promotes protein stability and regulates self-renewal in pancreatic cancer

Sharma

Gupta

Dauer

et al. 2018

Preprint

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Pancreatic cancer is among the 3rd leading cause of cancer related deaths in the United States along with a 5-year survival rate of 7%. The aggressive biology of the disease is responsible for such dismal outcome and is manifested by an increase in self-renewal capacity of the cancer cells, which leads to an increased rate of tumor-recurrence, contributing to poor prognosis. Transcription factor SOX2 maintains a critical balance between differentiation and “stemness” and is thus tightly regulated within a cell. In cancer, SOX2 is aberrantly “turned-on” leading to activation of self-renewal pathways in cancer. Regulation of Sox2 in cancer is poorly understood. In the current study, we show for the first time that in pancreatic cancer, Sox2 is modified by addition of O-GlcNAc moiety, catalyzed by OGT (O-GlcNAc Transferase) at S246. This activates Sox2 transcriptional activity by stabilizing the protein in the nucleus. A CRISPR-OGT knockout in pancreatic cancer cell line S2VP10 resulted in a delayed tumor initiation. We further showed that mutation of this site (S246A) prevents the modification of Sox2 and its downstream activity. Our study also demonstrated that targeting OGT in vivo with a small molecule inhibitor OSMI, results in decreased tumor burden, delayed tumor progression and a decreased expression of SOX2 in pancreatic cancer cells. Our study highlights for the first time that that the O-GlcNAc transferase dependent SOX2 glycosylation has a profound effect on the transcriptional activity of SOX2 and is instrumental in determining self-renewal in pancreatic cancer.SignificanceOur study highlights for the first time that that the O-GlcNAc transferase dependent SOX2 glycosylation determines self-renewal in pancreatic cancer which is responsible for tumor initiation.

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“…As a direct target, low density lipoprotein receptor-related protein 6 (LRP6) has been identified (96) (Figure 4). LRP6 together with LRP5 and the family of frizzled receptors are activating components of the wingless/integrated (WNT) signaling pathway (97)(98)(99). Calcipotriol has been identifed as a WNTpathway inhibitor targeting LRP6 (100).…”

Section: Down-regulated Mirs Mediating Metastasis In Pdac Xenograftsmentioning

confidence: 99%

Pancreatic Ductal Adenocarcinoma: MicroRNAs Affecting Tumor Growth and Metastasis in Preclinical In Vivo Models

Weidle

Birzele

Nopora

2019

Cancer Genomics Proteomics

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Modulation of post-translational modifications in β-catenin and LRP6 inhibits Wnt signaling pathway in pancreatic cancer

Cited by 44 publications

References 36 publications

The Novel Thienopyrimidine Derivative, RP-010, Produces Its Efficacy in Prostate Cancer Cells by Inducing the Fragmentation of β-catenin

The Novel Thienopyrimidine Derivative, RP-010, Produces Its Efficacy in Prostate Cancer Cells by Inducing the Fragmentation of β-catenin

O-GlcNAc modification of oncogenic transcription factor Sox2 promotes protein stability and regulates self-renewal in pancreatic cancer

Pancreatic Ductal Adenocarcinoma: MicroRNAs Affecting Tumor Growth and Metastasis in Preclinical In Vivo Models

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Modulation of post-translational modifications in β-catenin and LRP6 inhibits Wnt signaling pathway in pancreatic cancer

Cited by 44 publications

References 36 publications

The Novel Thienopyrimidine Derivative, RP-010, Produces Its Efficacy in Prostate Cancer Cells by Inducing the Fragmentation of &beta;-catenin

The Novel Thienopyrimidine Derivative, RP-010, Produces Its Efficacy in Prostate Cancer Cells by Inducing the Fragmentation of &beta;-catenin

O-GlcNAc modification of oncogenic transcription factor Sox2 promotes protein stability and regulates self-renewal in pancreatic cancer

Pancreatic Ductal Adenocarcinoma: MicroRNAs Affecting Tumor Growth and Metastasis in Preclinical In Vivo Models

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Product

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The Novel Thienopyrimidine Derivative, RP-010, Produces Its Efficacy in Prostate Cancer Cells by Inducing the Fragmentation of β-catenin

The Novel Thienopyrimidine Derivative, RP-010, Produces Its Efficacy in Prostate Cancer Cells by Inducing the Fragmentation of β-catenin