Cytoglobin inhibits migration through PI3K/AKT/mTOR pathway in fibroblast cells

Demirci, Selami; Doğan, Ayşegül; Apdik, Hüseyin; Tuysuz, Emre Can; Güllüoğlu, Şükrü; Bayrak, Ömer Faruk; Şahın, Fikrettin

doi:10.1007/s11010-017-3101-2

Cited by 21 publications

(11 citation statements)

References 57 publications

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“…As a member of the hexacoordinate globin superfamily, CYGB was shown to protect cells against hypoxic stress [15, 33], and inhibit the PI3K/AKT/mTOR pathway [34]. However, how CYGB suppresses tumor growth remains elusive.…”

Section: Discussionmentioning

confidence: 99%

The epigenetically downregulated factor CYGB suppresses breast cancer through inhibition of glucose metabolism

Feng

et al. 2018

J Exp Clin Cancer Res

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BackgroundRecent studies suggested the globin family member cytoglobin (CYGB) as a potential tumor suppressor; however, the mechanism by which CYGB suppresses cancer is elusive. We investigated the role and mechanism of CYGB in suppressing breast cancer.MethodsCYGB expression was examined by reverse transcription PCR, quantitative reverse transcription PCR and open database analysis. Promoter methylation was examined by methylation-specific PCR. Metabolomics and proteomics were analyzed by gas chromatography-mass spectrometry and isobaric tags for relative and absolute quantitation, respectively. The effects and mechanisms of ectopic CYGB expression in breast cancer cells were assessed with molecular biological and cellular approaches in vitro and with a xenograft tumor model in nude mice.ResultsCYGB expression was downregulated in breast cancer tissues and cell lines, which was associated with promoter methylation. Ectopic CYGB expression suppressed proliferation, migration, invasion and induced apoptosis in breast cancer cell lines MCF7 (p53WT) and MB231 (p53mt) in vitro, and inhibited xenograft tumor growth in vivo. By proteomics and metabolomics analysis, glucose metabolism was found to be one of the main pathways suppressed by CYGB. The CYGB-expressing cells had lower ATP and compromised glycolysis. Additionally, CYGB suppressed key glucose metabolism factors including GLUT1 and HXK2 in p53-dependent and -independent manners. Restoration of GLUT1 or HXK2 expression attenuated CYGB-mediated proliferation suppression and apoptosis induction.ConclusionsCYGB is a potential tumor suppressor in breast cancer that is epigenetically suppressed. The results for the first time suggest that CYGB suppresses breast cancer through inhibiting glucose metabolism, which could be exploited for breast cancer prevention and therapy.Electronic supplementary materialThe online version of this article (10.1186/s13046-018-0979-9) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

The epigenetically downregulated factor CYGB suppresses breast cancer through inhibition of glucose metabolism

Feng

et al. 2018

J Exp Clin Cancer Res

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“…CFU assay was performed to determine whether compound 5a affects the colony‐forming ability of cells as described previously (Demirci et al., ). Briefly, PC‐3, DU145 and LNCaP cells were seeded at a cell density of 100 cell per well of six‐well plates in the presence of respective IC 50 concentrations of compound 5a for each cell line.…”

Section: Methodsmentioning

confidence: 99%

Design and synthesis of phenylpiperazine derivatives as potent anticancer agents for prostate cancer

et al. 2019

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Novel thiourea (5a, 5b) and thiazolidinone derivatives (6a, 6b) were synthesized by hybridizing molecules starting from the compound 6‐(4‐phenylpiperazin‐1‐yl)pyridin‐3‐amine (4) which is known to show anticancer activity. The synthesis of the leading compound was carried out by using 1‐(5‐nitropyridin‐2‐yl)‐4‐phenylpiperazine (3) which was obtained by a novel method of the reaction of 2‐chloro‐5‐nitropyridine (1) and N‐phenylpiperazine (2). The structures of the compounds were confirmed using FTIR, 1H NMR, 13C NMR, HRMS spectroscopic methods and elemental analysis. The organic molecules were tested for their anticancer activities against prostate cancer (PC) cell lines: DU 145, PC‐3 and LNCaP. As the compound 5a exerted the highest cytotoxic activity, IC50 concentrations of compound 5a were further investigated in terms of morphology, colony‐forming ability, RNA expression, fragmented DNA and cell cycle distributions of PC cell lines. Overall data revealed that compound 5a treatment induces apoptosis and DNA fragmentation in PC cell lines and inhibits cell cycle progression resulting in the accumulation of cells in either the G1 or the S phases.

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“…Cygb is significantly deregulated by its promoter hypermethylation in most malignancies, 26,28,29 thereby promoting tumorigenesis and progression. [16][17][18][19][20][21][30][31][32] In this study, we found that Cygb is significantly deregulated in human HCC tissues, as compared with these adjacent non-tumor tissues and hepatolithiasis tissues ( Figure 1A-C), Cygb decrease promotes HCC proliferation, whereas Cygb restoration inhibits cell proliferation (Figure 2A-D). We proposed that Cytoglobin functions as tumor suppressor, and its decrease is negatively associated with HCC progression.…”

Section: Discussionmentioning

confidence: 64%

Cytoglobin ameliorates the stemness of hepatocellular carcinoma via coupling oxidative‐nitrosative stress signals

Zhang

Pei

Yang

et al. 2018

Molecular Carcinogenesis

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Cancer stem cells (CSCs) account for tumor self‐renewal and heterogeneity. Oxidative‐nitrosative stress (ONS) is an independent etiologic factor throughout tumorigenesis. Emerging evidences indicated that the interaction of ONS with CSCs contributes to tumor progression and resistance to chemoradiotherapy. Cytoglobin (Cygb) is a member of human hexacoordinate hemoglobin family and acts as a dynamic mediator of redox homeostasis. We observed that Cygb is significantly deregulated in human hepatocellular carcinoma (HCC) tissue and its decrease aggravates the growth of liver cancer stem cells (LCSCs) and increases the subpopulation of CD133(+) LCSCs. Cygb restoration inhibits HCC proliferation and LCSC growth, and decreases the subpopulation of CD133 (+) LCSCs in vitro. We found that Cygb absence promotes LCSC phenotypes and PI3 K/AKT activation, whereas Cygb restoration inhibits LCSC phenotypes and PI3 K/AKT activation. Furthermore, exogenous antioxidants can eliminate the inhibitory effect of Cygb to LCSC growth and phenotypes, as well as PI3 K/AKT activation. Collectively, this study demonstrated that cytoglobin functions as a tumor suppressor and targets CSCs at an ONS‐dependent manner. Thus, Cygb restoration could be a novel and promising therapeutic strategy against HCC with aberrant ROS/RNS accumulation.

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Cytoglobin inhibits migration through PI3K/AKT/mTOR pathway in fibroblast cells

Cited by 21 publications

References 57 publications

The epigenetically downregulated factor CYGB suppresses breast cancer through inhibition of glucose metabolism

The epigenetically downregulated factor CYGB suppresses breast cancer through inhibition of glucose metabolism

Design and synthesis of phenylpiperazine derivatives as potent anticancer agents for prostate cancer

Cytoglobin ameliorates the stemness of hepatocellular carcinoma via coupling oxidative‐nitrosative stress signals

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