RBP4-STRA6 Pathway Drives Cancer Stem Cell Maintenance and Mediates High-Fat Diet-Induced Colon Carcinogenesis

Karunanithi, Sellam; Levi, Liraz; DeVecchio, Jennifer; Karagkounis, G.; Reizes, Ofer; Lathia, Justin D.; Kalady, Matthew F.; Noy, Noa

doi:10.1016/j.stemcr.2017.06.002

Cited by 82 publications

(69 citation statements)

References 48 publications

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“…This observation correlates with epidemiological studies showing that different types of diets modulate the risk to develop intestinal cancers [11,12], with high fat containing diets leading to higher prevalence for the development of colon cancers [13,14]. Here, deregulated stem cell activities appear to be directly associated with alterations in intestinal JAK/STAT signaling [15].…”

Section: Introductionsupporting

confidence: 84%

A high-fat diet induces a microbiota-dependent increase in stem cell activity in the Drosophila intestine

Frieling

Faisal

Sporn

et al. 2019

Preprint

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18Over-consumption of high-fat diets (HFDs) is associated with several pathologies. Although 19 the intestine is the organ that comes into direct contact with all diet components, the 20 impact of HFD has mostly been studied in organs that are linked to obesity and obesity 21 related disorders. We used Drosophila as a simple model to disentangle the effects of a HFD 22 activation. Surprisingly, we found that a HFD triggered induced stem cell activation 48 critically depends on the indigenous microbiota, as in germ free flies this reaction was 49 completely abolished. Moreover, HFD changed both, composition and abundance of the 50 microbiota. As fecal transfer experiments failed to recapitulate the HFD phenotype, we 51 assume that the increased bacterial load is the major cause for the HFD triggered stem cell 52 activation in the intestine. 53 54 55 High-fat diets induce stem cell activation

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Section: Introductionsupporting

confidence: 84%

A high-fat diet induces a microbiota-dependent increase in stem cell activity in the Drosophila intestine

Frieling

Faisal

Sporn

et al. 2019

Preprint

View full text Add to dashboard Cite

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“…317,318 Moreover, studies have also found aberrant activation of STATs in human cancers, such as head and neck cancer, 319 endometrial cancer, 320 breast cancer, diffuse large B cell lymphoma, 321 HCC, 322 colorectal cancer, glioma, 323 and colon cancer. 324 Furthermore, aberrant STAT5 signaling has been found in the pathogenesis of hematologic and solid organ malignancies. 325,326 The JAK/STAT pathway is evolutionarily conserved.…”

Section: Major Signaling Pathways In Cscsmentioning

confidence: 99%

Targeting cancer stem cell pathways for cancer therapy

Yang

Shi

Zhao

et al. 2020

Sig Transduct Target Ther

1,246

998

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Since cancer stem cells (CSCs) were first identified in leukemia in 1994, they have been considered promising therapeutic targets for cancer therapy. These cells have self-renewal capacity and differentiation potential and contribute to multiple tumor malignancies, such as recurrence, metastasis, heterogeneity, multidrug resistance, and radiation resistance. The biological activities of CSCs are regulated by several pluripotent transcription factors, such as OCT4, Sox2, Nanog, KLF4, and MYC. In addition, many intracellular signaling pathways, such as Wnt, NF-κB (nuclear factor-κB), Notch, Hedgehog, JAK-STAT (Janus kinase/signal transducers and activators of transcription), PI3K/AKT/mTOR (phosphoinositide 3-kinase/AKT/mammalian target of rapamycin), TGF (transforming growth factor)/SMAD, and PPAR (peroxisome proliferator-activated receptor), as well as extracellular factors, such as vascular niches, hypoxia, tumor-associated macrophages, cancer-associated fibroblasts, cancer-associated mesenchymal stem cells, extracellular matrix, and exosomes, have been shown to be very important regulators of CSCs. Molecules, vaccines, antibodies, and CAR-T (chimeric antigen receptor T cell) cells have been developed to specifically target CSCs, and some of these factors are already undergoing clinical trials. This review summarizes the characterization and identification of CSCs, depicts major factors and pathways that regulate CSC development, and discusses potential targeted therapy for CSCs.Signal Transduction and Targeted Therapy (2020) 5:8; https://doi.

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“…There is growing evidence associating colon cancer development with environmental causes, such as a high-fat diet [6]. Pro-obesity diets enhance the numbers and function of the Lgr5 + stem cells and/or colon tumorigenesis by activating multiple pathways, including peroxisome proliferator-activated receptor delta (PPAR-δ) and Wnt/β-catenin signatures [7], retinol binding protein 4 (RBP4)-stimulated by the retinoic acid 6 (STRA6) pathway [8], and fatty acid oxidation [9]. Similar changes were observed when dietary constituents, such as palmitic acid and oleic acid (OA), were administered, suggesting a critical role for fatty acid in the maintenance of colon CSCs.…”

Section: Introductionmentioning

confidence: 99%

Inhibition of Stearoyl-CoA Desaturase-1 Activity Suppressed SREBP Signaling in Colon Cancer Cells and Their Spheroid Growth

Qin

Kojima

2019

Gastrointestinal Disorders

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Unsaturated fatty acids are critical in promoting colon tumorigenesis and its stemness. Stearoyl-CoA desaturase-1 (SCD1) is a rate-limiting lipid desaturase associated with colon cancer cell proliferation and metastasis control. This study aims to evaluate the effects of SCD1 inhibition on colon cancer spheroid growth in a three-dimensional cell culture system. An analysis of clinical data showed that increased SCD1 gene expression in colon tumors was negatively correlated with the prognosis. A chemical inhibitor of SCD1, CAY10566, inhibited the growth of colon cancer cells in both monolayer and sphere cultures. In addition, oleic acid administration-a monounsaturated fatty acid generated by the action of SCD1-prevented the suppression of sphere formation by CAY10566. RNA-sequencing data from 382 colon tumor patient samples obtained from the Cancer Genome Atlas database showed that 806 genes were SCD1-associated genes in human colon cancer. Correlation analysis identified the master regulator of lipid homeostasis sterol regulatory element-binding protein 2 (SREBP2) as a prominent transcription factor, whose expression was positively correlated with SCD1 in human colon cancer. SCD1 knockdown using siRNA in colon cancer samples, suppressed SREBP2 gene expression, providing direct evidence that SREBP signaling is under the control of SCD1 in these cells. Pathway analysis in the Ingenuity Pathways Analysis platform showed that SCD1 expression positively correlated with genes involved in multiple pathways, including lipid synthesis and incorporation, cell proliferation, and tissue tumorigenesis. Further network analysis revealed a central role for Myc in the network hierarchy of the SCD1-correlated genes. These findings suggested that SCD1 inhibition would be an effective strategy for suppressing colon cancer spheroid growth, partly through downregulating SREBP-mediated lipid and cholesterol metabolism and Myc signaling. Author Contributions: Study conceptualization, X.-Y.Q. and S.K.; methodology/formal analysis/investigation, X.-Y.Q.; writing, X.-Y.Q. and S.K.; supervision, S.K.; and funding acquisition, X.-Y.Q. and S.K.

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RBP4-STRA6 Pathway Drives Cancer Stem Cell Maintenance and Mediates High-Fat Diet-Induced Colon Carcinogenesis

Cited by 82 publications

References 48 publications

A high-fat diet induces a microbiota-dependent increase in stem cell activity in the Drosophila intestine

A high-fat diet induces a microbiota-dependent increase in stem cell activity in the Drosophila intestine

Targeting cancer stem cell pathways for cancer therapy

Inhibition of Stearoyl-CoA Desaturase-1 Activity Suppressed SREBP Signaling in Colon Cancer Cells and Their Spheroid Growth

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