Intersection of retinoblastoma tumor suppressor function, stem cells, metabolism, and inflammation

Kitajima, Shunsuke; Takahashi, Chiaki

doi:10.1111/cas.13312

Cited by 39 publications

(40 citation statements)

References 80 publications

(174 reference statements)

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“…STAT3 is considered to be an important regulator of CSCs [45,46]. It is a transcription factor that directly regulates the gene expression of some CSC markers by binding to the promoters of SALL4, Sox2, Oct4, and Nanog [47][48][49].…”

Section: Discussionmentioning

confidence: 99%

PGD2/PTGDR2 Signaling Restricts the Self-Renewal and Tumorigenesis of Gastric Cancer

Zhang

Bie

et al. 2018

Stem Cells

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The antitumor effect of prostaglandin D2 (PGD2) on gastric cancer (GC) has been known for decades. However, the mechanism of PGD2's control of GC growth is unclear. Cancer stem cells (CSCs) are implicated in tumor neovascularization, invasiveness, and therapeutic resistance. Herein, we discovered that signaling between PGD2 and its receptor (PTGDR2) has the ability to restrict the self-renewal of GC cells in vitro and suppress tumor growth and metastasis in vivo. To obtain these findings, we first determined that PGD2 synthase (L-PTGDS) and PTGDR2 expression were lower in GC tissues than adjacent tissues and was associated with the patients' prognosis. Moreover, the expression of L-PTGDS and PTGDR2 was negatively correlated with the GC-CSC markers Sall4 and Lgr5 in GC tissues. Second, L-PTGDS and PTGDR2 expression were knocked down in CSC-like cells, resulting in enhanced expression of CSC markers and self-renewal ability. Direct PGD2 stimulation and L-PTGDS overexpression produced the opposite effect. Thirdly, PGD2 inhibited tumor growth and incidence rate in a subcutaneous tumor model and suppressed liver and mesenteric metastasis in a peritoneal metastasis model. Interfering with the expression of PTGDR2 reversed these effects in vivo. Last, a mechanistic study found that PGD2 inhibited STAT3 phosphorylation and nuclear expression. Further experiments revealed that the inhibitory effect of PGD2 on the expression of CSC markers disappeared after mutations were introduced into STAT3 phosphorylation (Thr705) site. In short, this study reveals a novel function of PGD2/PTGDR2 signaling on CSC regulation and provides a new way to control the development of GC. Stem Cells 2018;36:990-1003.

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Section: Discussionmentioning

confidence: 99%

PGD2/PTGDR2 Signaling Restricts the Self-Renewal and Tumorigenesis of Gastric Cancer

Zhang

Bie

et al. 2018

Stem Cells

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“…The progression of the cell cycle is regulated by the cyclin/cyclin-dependent kinase (CDKs) complex. The cyclin D-CDK4/6 complex takes center role in G1/S transition and its binding activates CDKs which then phosphorylate retinoblastoma (RB); a major suppressor protein of G1/S transition [7,8].…”

Section: Tcf19 Enhances Cell Proliferation In Hepatocellular Carcinommentioning

confidence: 99%

TCF19 enhances cell proliferation in hepatocellular carcinoma by activating the ATK/FOXO1 signaling pathway

Zeng¹,

Feng²,

Zhao³

et al. 2019

neo

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Hepatocellular carcinoma (HCC) is one of the most lethal malignancies because of its complexity, high metastasis, recurrence and limited treatment options. Reports state that transcription factor 19 (TCF19) is related to the susceptibility to chronic HBV infection and that it strongly increases the risk of HCC occurrence, but its molecular mechanisms remain unknown. This study analyzed the datasets and confirmed that TCF19 is significantly increased in HCC cell lines and tissues. MTT and colony formation assay revealed that TCF19 over-expression enhances cell proliferation and tumorigenesis. Flow cytometry assay then determined that TCF over-expression helps HCC cell G1/S phase transition, and further research showed that TCF19 up-regulation inhibits p57 Kip2 , p21 Cip1 and p27 Kip1 cell cycle suppressors, enhances the expression of cyclin D1 expression and simulates retinoblastoma (Rb), FOXO1 and AKT phosphorylation. In addition, AKT and FOXO1 inhibitors suppress the TCF19 effect on cell proliferation. This demonstrates that AKT/FOXO1 signaling is essential for TCF19 influence on HCC progression, and our combined results suggest that crucial links between TCF19 and HCC can provide a novel target for hepatocellular carcinoma treatment.

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“…The role of pRb in immunity has been well described [31,32], with recent studies demonstrating that pRb inactivation recruits tumor-associated macrophages and immunosuppressive myeloid-derived suppressor cells within the tumor microenvironment (TME) [33]. This was found to be due to increased cytokine/chemokine secretion through altered AMP-activated protein kinase signaling from increased fatty acid oxidation.…”

Section: Discussionmentioning

confidence: 99%

Loss of Rb1 Enhances Glycolytic Metabolism in Kras-Driven Lung Tumors In Vivo

Conroy

Dougherty

Kruer

et al. 2020

Cancers

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Dysregulated metabolism is a hallmark of cancer cells and is driven in part by specific genetic alterations in various oncogenes or tumor suppressors. The retinoblastoma protein (pRb) is a tumor suppressor that canonically regulates cell cycle progression; however, recent studies have highlighted a functional role for pRb in controlling cellular metabolism. Here, we report that loss of the gene encoding pRb (Rb1) in a transgenic mutant Kras-driven model of lung cancer results in metabolic reprogramming. Our tracer studies using bolus dosing of [U-13C]-glucose revealed an increase in glucose carbon incorporation into select glycolytic intermediates. Consistent with this result, Rb1-depleted tumors exhibited increased expression of key glycolytic enzymes. Interestingly, loss of Rb1 did not alter mitochondrial pyruvate oxidation compared to lung tumors with intact Rb1. Additional tracer studies using [U-13C,15N]-glutamine and [U-13C]-lactate demonstrated that loss of Rb1 did not alter glutaminolysis or utilization of circulating lactate within the tricarboxylic acid cycle (TCA) in vivo. Taken together, these data suggest that the loss of Rb1 promotes a glycolytic phenotype, while not altering pyruvate oxidative metabolism or glutamine anaplerosis in Kras-driven lung tumors.

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Intersection of retinoblastoma tumor suppressor function, stem cells, metabolism, and inflammation

Cited by 39 publications

References 80 publications

PGD2/PTGDR2 Signaling Restricts the Self-Renewal and Tumorigenesis of Gastric Cancer

PGD2/PTGDR2 Signaling Restricts the Self-Renewal and Tumorigenesis of Gastric Cancer

TCF19 enhances cell proliferation in hepatocellular carcinoma by activating the ATK/FOXO1 signaling pathway

Loss of Rb1 Enhances Glycolytic Metabolism in Kras-Driven Lung Tumors In Vivo

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