scholarly journals Synthetic essentiality of metabolic regulator PDHK1 in PTEN-deficient cells and cancers

2018 ◽  
Author(s):  
Nilanjana Chatterjee ◽  
Evangelos Pazarentzos ◽  
Gorjan Hrustanovic ◽  
Luping Lin ◽  
Erik Verschueren ◽  
...  
Keyword(s):  
Tumor Suppressor ◽  
Signaling Pathway ◽  
Protein Phosphatase ◽  
Clinical Relevance ◽  
Patient Survival ◽  
Tumor Regression ◽  
Essential Gene ◽  
Aerobic Glycolysis ◽  
Pten Protein

SUMMARYPTEN is a tumor suppressor that is often inactivated in cancer and possesses both lipid and protein phosphatase activities. We report the metabolic regulator PDHK1 (pyruvate dehydrogenase kinase1) is a synthetic-essential gene in PTEN-deficient cancer and normal cells. The predominant mechanism of PDHK1 regulation and dependency is the PTEN protein phosphatase dephosphorylates NFκ;B activating protein (NKAP) and limits NFκB activation to suppress expression of PDHK1, a NFκB target gene. Loss of the PTEN protein phosphatase upregulates PDHK1 to drive aerobic glycolysis and induce PDHK1 cellular dependence. PTEN-deficient human tumors harbor increased PDHK1, which is a biomarker of decreased patient survival, establishing clinical relevance. This study uncovers a PTEN-regulated signaling pathway and reveals PDHK1 as a potential target in PTEN-deficient cancers.SIGNIFICANCEThe tumor suppressor PTEN is widely inactivated in cancers and tumor syndromes. PTEN antagonizes PI3K/AKT signaling via its lipid phosphatase activity. The modest success of PI3K/AKT inhibition in PTEN-deficient cancer patients provides rationale for identifying other vulnerabilities in PTEN-deficient cancers to improve clinical outcomes. We show that PTEN-deficient cells are uniquely sensitive to PDHK1 inhibition. PTEN and PDHK1 co-suppression reduced colony formation and induced cell deathin vitroand tumor regressionin vivo. PDHK1 levels were high in PTEN-deficient patient tumors and associated with inferior patient survival, establishing clinical relevance. Our study identifies a PTEN-regulated signaling pathway linking the PTEN protein phosphatase to the metabolic regulator PDHK1 and provides a mechanistic basis for PDHK1 targeting in PTEN-deficient cancers.

scholarly journals MicroRNA-1297 suppressed the Akt/GSK3β signaling pathway and stimulated neural apoptosis in an in vivo sevoflurane exposure model

2021 ◽  
Vol 49 (4) ◽  
pp. 030006052098210
Author(s):  
Quan Wang ◽  
Jingcong Luo ◽  
Ruiqiang Sun ◽  
Jia Liu
Keyword(s):  
Protein Expression ◽  
Signaling Pathway ◽  
Neuronal Apoptosis ◽  
In Vitro Model ◽  
Nervous System Development ◽  
Exposure Model ◽  
Control Group ◽  
Pten Protein ◽  
Vitro Model

Objective Common inhalation anesthetics used for clinical anesthesia (such as sevoflurane) may induce nerve cell apoptosis during central nervous system development. Furthermore, anesthetics can produce cognitive impairments, such as learning and memory impairments, that continue into adulthood. However, the precise mechanism remains largely undefined. We aimed to determine the function of microRNA-1297 (miR-1297) in sevoflurane-induced neurotoxicity. Methods Reverse transcription-polymerase chain reaction assays were used to analyze miR-1297 expression in sevoflurane-exposed mice. MTT and lactate dehydrogenase (LDH) assays were used to measure cell growth, and neuronal apoptosis was analyzed using flow cytometry. Western blot analyses were used to measure PTEN, PI3K, Akt, and GSK3β protein expression. Results In sevoflurane-exposed mice, miR-1297 expression was up-regulated compared with the control group. MiR-1297 up-regulation led to neuronal apoptosis, inhibition of cell proliferation, and increased LDH activity in the in vitro model of sevoflurane exposure. MiR-1297 up-regulation also suppressed the Akt/GSK3β signaling pathway and induced PTEN protein expression in the in vitro model. PTEN inhibition (VO-Ohpic trihydrate) reduced PTEN protein expression and decreased the effects of miR-1297 down-regulation on neuronal apoptosis in the in vitro model. Conclusion Collectively, the results indicated that miR-1297 stimulates sevoflurane-induced neurotoxicity via the Akt/GSK3β signaling pathway by regulating PTEN expression.

scholarly journals GSTZ1 deficiency promotes hepatocellular carcinoma proliferation via activation of the KEAP1/NRF2 pathway

2019 ◽  
Vol 38 (1) ◽  
Author(s):  
Jingjing Li ◽  
Qiujie Wang ◽  
Yi Yang ◽  
Chong Lei ◽  
Fan Yang ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Signaling Pathway ◽  
Aerobic Glycolysis ◽  
Hepatoma Cell ◽  
Related Factor ◽  
Promising Therapeutic Approach ◽  
Nrf2 Signaling Pathway ◽  
Hcc Cells

Abstract Background Glutathione S-transferase zeta 1 (GSTZ1) is the penultimate enzyme in phenylalanine/tyrosine catabolism. GSTZ1 is dysregulated in cancers; however, its role in tumorigenesis and progression of hepatocellular carcinoma (HCC) is largely unknown. We aimed to assess the role of GSTZ1 in HCC and to reveal the underlying mechanisms, which may contribute to finding a potential therapeutic strategy against HCC. Methods We first analyzed GSTZ1 expression levels in paired human HCC and adjacent normal tissue specimens and the prognostic effect of GSTZ1 on HCC patients. Thereafter, we evaluated the role of GSTZ1 in aerobic glycolysis in HCC cells on the basis of the oxygen consumption rate (OCR) and extracellular acidification rate (ECAR). Furthermore, we assessed the effect of GSTZ1 on HCC proliferation, glutathione (GSH) concentration, levels of reactive oxygen species (ROS), and nuclear factor erythroid 2-related factor 2 (NRF2) signaling via gain- and loss- of GSTZ1 function in vitro. Moreover, we investigated the effect of GSTZ1 on diethylnitrosamine (DEN) and carbon tetrachloride (CCl4) induced hepatocarcinogenesis in a mouse model of HCC. Results GSTZ1 was downregulated in HCC, thus indicating a poor prognosis. GSTZ1 deficiency significantly promoted hepatoma cell proliferation and aerobic glycolysis in HCC cells. Moreover, loss of GSTZ1 function depleted GSH, increased ROS levels, and enhanced lipid peroxidation, thus activating the NRF2-mediated antioxidant pathway. Furthermore, Gstz1 knockout in mice promoted DEN/CCl4-induced hepatocarcinogenesis via activation of the NRF2 signaling pathway. Furthermore, the antioxidant agent N-acetylcysteine and NRF2 inhibitor brusatol effectively suppressed the growth of Gstz1-knockout HepG2 cells and HCC progression in Gstz1−/− mice. Conclusions GSTZ1 serves as a tumor suppressor in HCC. GSH depletion caused by GSTZ1 deficiency elevates oxidative stress, thus constitutively activating the NRF2 antioxidant response pathway and accelerating HCC progression. Targeting the NRF2 signaling pathway may be a promising therapeutic approach for this subset of HCC.

scholarly journals ZMYND10, an epigenetically regulated tumor suppressor, exerts tumor-suppressive functions via miR145-5p/NEDD9 axis in breast cancer

2019 ◽  
Vol 11 (1) ◽  
Author(s):  
Yan Wang ◽  
Liangying Dan ◽  
Qianqian Li ◽  
Lili Li ◽  
Lan Zhong ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Tumor Suppressor ◽  
Signaling Pathway ◽  
Cancer Metastasis ◽  
Ectopic Expression ◽  
Migration And Invasion ◽  
Breast Cancer Cell Lines ◽  
Multiple Tumor

Abstract Background Recent studies suggested that ZMYND10 is a potential tumor suppressor gene in multiple tumor types. However, the mechanism by which ZMYND10 inhibits breast cancer remains unclear. Here, we investigated the role and mechanism of ZMYND10 in breast cancer inhibition. Results ZMYND10 was dramatically reduced in multiple breast cancer cell lines and tissues, which was associated with promoter hypermethylation. Ectopic expression of ZMYND10 in silenced breast cancer cells induced cell apoptosis while suppressed cell growth, cell migration and invasion in vitro, and xenograft tumor growth in vivo. Furthermore, molecular mechanism studies indicated that ZMYND10 enhances expression of miR145-5p, which suppresses the expression of NEDD9 protein through directly targeting the 3'-untranslated region of NEDD9 mRNA. Conclusions Results from this study show that ZMYND10 suppresses breast cancer tumorigenicity by inhibiting the miR145-5p/NEDD9 signaling pathway. This novel discovered signaling pathway may be a valid target for small molecules that might help to develop new therapies to better inhibit the breast cancer metastasis.

scholarly journals The Novel Tumor Suppressor Gene ZNF24 Induces THCA Cells Senescence by Regulating Wnt Signaling Pathway, Resulting in Inhibition of THCA Tumorigenesis and Invasion

2021 ◽  
Vol 11 ◽  
Author(s):  
Juan Xiong ◽  
Panpan Jiang ◽  
Li Zhong ◽  
Youling Wang
Keyword(s):  
Tumor Suppressor ◽  
Wnt Signaling ◽  
Signaling Pathway ◽  
Nude Mice ◽  
Treatment Options ◽  
Ectopic Expression ◽  
Wnt Signaling Pathway ◽  
Migration And Invasion

ObjectClinically, the effective treatment options available to thyroid cancer (THCA) patients are very limited. Elucidating the features of tumor suppressor genes (TSGs) and the corresponding signal transduction cascade may provide clues for the development of new strategies for targeted therapy of THCA. Therefore, this paper aims to explore the mechanism of ZNF24 underlying promoting THCA cell senescence at molecular level.MethodsWe performed RT-PCR and Western Blotting for evaluating associated RNA and protein expression. CCK8, colony forming, wound healing and Transwell chamber assays were conducted to examine THCA cell proliferation, invasion and migration. β-galactosidase staining assay was performed to detect THCA cells senescence. The size and volume of xenotransplanted tumors in nude mice are calculated to asses ZNF24 effect in vivo.ResultsEctopic expression of ZNF24 significantly inhibited the cell viability, colony forming, migration and invasion abilities of THCA cell lines (K1/GLAG-66i and BCPAPi) (P < 0.05). ZNF24 induced BCPAPi cells senescence through regulating Wnt signaling pathway. ZNF24 inhibited Wnt signaling pathway activition by competitively binding β-catenin from LEF1/TCF1-β-catenin complex. In nude mice, both Ectopic expression of ZNF24 and 2,4-Da (the strong β-catenin/Tcf-4 inhibitor) treatment significantly decreased both the size and weight of xenotransplanted tumors when compared with control mice (P < 0.05).ConclusionResults obtained in vivo and in vitro reveal the role of ZNF24 in significantly suppressing THCA tumorigenesis and invasion by regulating Wnt signaling pathway.

scholarly journals The nuclear transport receptor Importin-11 is a tumor suppressor that maintains PTEN protein

2017 ◽  
Vol 216 (3) ◽  
pp. 641-656 ◽  
Author(s):  
Muhan Chen ◽  
Dawid G. Nowak ◽  
Navneet Narula ◽  
Brian Robinson ◽  
Kaitlin Watrud ◽  
...  
Keyword(s):  
Tumor Suppressor ◽  
Disease Recurrence ◽  
Limiting Factor ◽  
Special Importance ◽  
Pten Protein ◽  
Protein Levels ◽  
Mouse Prostate ◽  
Transport Receptor

Phosphatase and tensin homologue (PTEN) protein levels are critical for tumor suppression. However, the search for a recurrent cancer-associated gene alteration that causes PTEN degradation has remained futile. In this study, we show that Importin-11 (Ipo11) is a transport receptor for PTEN that is required to physically separate PTEN from elements of the PTEN degradation machinery. Mechanistically, we find that the E2 ubiquitin-conjugating enzyme and IPO11 cargo, UBE2E1, is a limiting factor for PTEN degradation. Using in vitro and in vivo gene-targeting methods, we show that Ipo11 loss results in degradation of Pten, lung adenocarcinoma, and neoplasia in mouse prostate with aberrantly high levels of Ube2e1 in the cytoplasm. These findings explain the correlation between loss of IPO11 and PTEN protein in human lung tumors. Furthermore, we find that IPO11 status predicts disease recurrence and progression to metastasis in patients choosing radical prostatectomy. Thus, our data introduce the IPO11 gene as a tumor-suppressor locus, which is of special importance in cancers that still retain at least one intact PTEN allele.

Protein Phosphatase 2A Is Involved in the Regulation of Protein Kinase A Signaling Pathway during in Vitro Chondrogenesis

2002 ◽  
Vol 275 (1) ◽  
pp. 1-8 ◽  
Author(s):  
Róza Zákány ◽  
Kornélia Szűcs ◽  
Éva Bakó ◽  
Szabolcs Felszeghy ◽  
Gabriella Czifra ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Protein Kinase A ◽  
Signaling Pathway ◽  
Protein Phosphatase ◽  
Protein Phosphatase 2A ◽  
Phosphatase 2A ◽  
Kinase A

scholarly journals Krüppel-like factor 8 promotes aerobic glycolysis in prostate cancer cells by regulating AKT/mTOR signaling pathway

2020 ◽  
Vol 19 (10) ◽  
pp. 2091-2096
Author(s):  
Cunming Zhang ◽  
Song Chen ◽  
Lide Song ◽  
Haibo Ye ◽  
Junwei Wang
Keyword(s):  
Prostate Cancer ◽  
Cell Viability ◽  
Signaling Pathway ◽  
Therapeutic Target ◽  
Aerobic Glycolysis ◽  
Lactic Acid Production ◽  
Mtor Signaling ◽  
Cell Counting ◽  
Mtor Signaling Pathway

Purpose: To investigate the effects of Krüppel-like factor 8 (KLF8) in prostate cancer (PCa) cell viability and glycolysis, and explore its role as a regulatory factor.Methods: Immunoblot assays were conducted to assess the expression of KLF8 and proteins in AKT/mTOR pathway in PCa cell lines PC-3 and DU145. Cell Counting Kit-8 assays were performed to assess the effect of KLF8 on PCa cell viability. The glycolysis capacity of PCa cells was determined by measuring the levels of glucose intake, lactic acid production, and cellular ATP levels.Results: Depletion of KLF8 decreased the survival of PCa cells in vitro (p < 0.05). KLF8 depletion also inhibited aerobic glucose metabolism in PCa cells (p < 0.05). Further studies confirmed that KLF8 contributed to the growth and glycolysis of PCa cells via the regulation of AKT/mTOR pathway.Conclusion: KLF8 regulates glycolysis in PCa cells by regulating AKT/mTOR signaling pathway and is thus a promising therapeutic target for PCa treatment. Keywords: Krüppel-like factor 8 (KLF8), Prostate cancer (PCa), Aerobic glucose, AKT/mTOR signaling pathway, Therapeutic target

scholarly journals Mitochondrial dysfunction induces radioresistance in colorectal cancer by activating [Ca2+]m-PDP1-PDH-histone acetylation retrograde signaling

2021 ◽  
Vol 12 (9) ◽  
Author(s):  
Yingying Shi ◽  
You Wang ◽  
Huangang Jiang ◽  
Xuehua Sun ◽  
Hui Xu ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Mitochondrial Dysfunction ◽  
Histone Acetylation ◽  
Complex I ◽  
Tumor Regression ◽  
Aerobic Glycolysis ◽  
Metabolic Reprogramming ◽  
Retrograde Signaling ◽  
Neoadjuvant Radiotherapy

AbstractMitochondrial retrograde signaling (mito-RTG) triggered by mitochondrial dysfunction plays a potential role in regulating tumor metabolic reprogramming and cellular sensitivity to radiation. Our previous studies showed phos-pyruvate dehydrogenase (p-PDH) and PDK1, which involved in aerobic glycolysis, were positively correlated with radioresistance, but how they initiate and work in the mito-RTG pathway is still unknown. Our further genomics analysis revealed that complex I components were widely downregulated in mitochondrial dysfunction model. In the present study, high expression of p-PDH was found in the complex I deficient cells and induced radioresistance. Mechanistically, complex I defects led to a decreased PDH both in cytoplasm and nucleus through [Ca2+]m-PDP1-PDH axis, and decreased PDH in nucleus promote DNA damage repair (DDR) response via reducing histone acetylation. Meanwhile, NDUFS1 (an important component of the complex I) overexpression could enhance the complex I activity, reverse glycolysis and resensitize cancer cells to radiation in vivo and in vitro. Furthermore, low NDUFS1 and PDH expression were validated to be correlated with poor tumor regression grading (TRG) in local advanced colorectal cancer (CRC) patients underwent neoadjuvant radiotherapy. Here, we propose that the [Ca2+]m-PDP1-PDH-histone acetylation retrograde signaling activated by mitochondrial complex I defects contribute to cancer cell radioresistance, which provides new insight in the understanding of the mito-RTG. For the first time, we reveal that NDUFS1 could be served as a promising predictor of radiosensitivity and modification of complex I function may improve clinical benefits of radiotherapy in CRC.

scholarly journals Novel IL-21 signaling pathway up-regulates c-Myc and induces apoptosis of diffuse large B-cell lymphomas

Blood ◽  
2010 ◽  
Vol 115 (3) ◽  
pp. 570-580 ◽  
Author(s):  
Kristopher A. Sarosiek ◽  
Raquel Malumbres ◽  
Hovav Nechushtan ◽  
Andrew J. Gentles ◽  
Eli Avisar ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Signaling Pathway ◽  
De Novo ◽  
Tumor Regression ◽  
B Cell Lymphoma ◽  
Primary Tumors ◽  
Regulatory Effects ◽  
Large B Cell

Abstract Interleukin-21 (IL-21), a member of the IL-2 cytokine family, has diverse regulatory effects on natural killer (NK), T, and B cells. In contrast to other cytokines that are usually immunostimulatory, IL-21 can induce apoptosis of murine B cells at specific activation-differentiation stages. This effect may be used for treatment of B-cell malignancies. Herein we report that diffuse large B-cell lymphoma (DLBCL) cell lines exhibit widespread expression of the IL-21 receptor (IL-21R) and that IL-21 stimulation leads to cell-cycle arrest and caspase-dependent apoptosis. IL-21 also induces apoptosis in de novo DLBCL primary tumors but does not affect viability of human healthy B cells. Furthermore, IL-21 promotes tumor regression and prolongs survival of mice harboring xenograft DLBCL tumors. The antilymphoma effects of this cytokine are dependent on a mechanism involving IL-21–activated signal transducer and activator of transcription 3 (STAT3) up-regulating expression of c-Myc. This up-regulation promotes a decrease in expression of antiapoptotic Bcl-2 and Bcl-XL proteins triggering cell death. Our results represent one of the first examples in which the STAT3–c-Myc signaling pathway, which can promote survival and oncogenesis, can induce apoptosis in neoplastic cells. Moreover, based on IL-21's potency in vitro and in animal models, our findings indicate that this cytokine should be examined in clinical studies of DLBCL.

Sign in / Sign up

Export Citation Format

Share Document