Silibinin inhibits hypoxia-inducible factor-1alpha and mTOR/p70S6K/4E-BP1 signalling pathway in human cervical and hepatoma cancer cells: implications for anticancer therapy.


:The hypoxia-inducible factor 1 (HIF-1) plays a critical role for tumour adaptation to microenvironmental hypoxia, and represents an appealing chemotherapeutic target. Silibinin is a nontoxic flavonoid reported to exhibit anticancer properties. However, the mechanisms by which silibinin inhibits tumour growth are not fully understood. In this study, silibinin was found to inhibit hypoxia-induced HIF-1alpha accumulation and HIF-1 transcriptional activity in human cervical (HeLa) and hepatoma (Hep3B) cells. Neither HIF-1alpha protein degradation rate nor HIF-1alpha steady-state mRNA level was affected by silibinin. Rather, we found that suppression of HIF-1alpha accumulation by silibinin correlated with strong dephosphorylation of mammalian target of rapamycin (mTOR) and its effectors ribosomal protein S6 kinase (p70S6K) and eukaryotic initiation factor 4E-binding protein-1 (4E-BP1), a pathway known to regulate HIF-1alpha expression at the translational level. Silibinin also activated Akt, a mechanistic feature exhibited by established mTOR inhibitors in many tumour cells. Moreover, silibinin reduced hypoxia-induced vascular endothelial growth factor (VEGF) release by HeLa and Hep3B cells, and this effect was potentiated by the PI3K/Akt inhibitor LY294002. Finally, silibinin was found to be a potent inhibitor of cell proliferation. These results show that silibinin is an effective inhibitor of HIF-1 and provide new perspectives into the mechanism of its anticancer activity.






García-Maceira P,Mateo J




Has Abstract


2009-01-22 00:00:00
















  • The autophagic paradox in cancer therapy.

    abstract::Autophagy, hallmarked by the formation of double-membrane bound organelles known as autophagosomes, is a lysosome-dependent pathway for protein degradation. The role of autophagy in carcinogenesis is context dependent. As a tumor-suppressing mechanism in early-stage carcinogenesis, autophagy inhibits inflammation and ...


    pub_type: 杂志文章,评审


    authors: Wu WK,Coffelt SB,Cho CH,Wang XJ,Lee CW,Chan FK,Yu J,Sung JJ

    更新日期:2012-02-23 00:00:00

  • IL-6-independent expression of Mcl-1 in human multiple myeloma.

    abstract::Mcl-1 is a critical antiapoptotic survival factor for human multiple myeloma (MM). We examined the importance of IL-6 for Mcl-1 expression in five MM cell lines and in primary MM cells from 14 patients. While culture of MM.1S cells in IL-6 did induce Mcl-1 expression, four other MM cell lines exhibited high levels of ...


    pub_type: 杂志文章


    authors: Zhang B,Potyagaylo V,Fenton RG

    更新日期:2003-03-27 00:00:00

  • The PR status of the originating cell of ER/PR-negative mouse mammary tumors.

    abstract::Progesterone receptor (PR) is usually co-localized with estrogen receptor (ER) in normal mammary cells. It is not known whether ER/PR-negative human breast cancer arises from an ER/PR-negative cell or from an ER/PR-positive cell that later lost ER/PR. Using intraductal injection of a lentivirus to deliver both an onco...


    pub_type: 杂志文章


    authors: Dong J,Zhao W,Shi A,Toneff M,Lydon J,So D,Li Y

    更新日期:2016-08-04 00:00:00

  • p21 suppresses inflammation and tumorigenesis on pRB-deficient stratified epithelia.

    abstract::The retinoblastoma gene product (pRb) controls proliferation and differentiation processes in stratified epithelia. Importantly, and in contrast to other tissues, Rb deficiency does not lead to spontaneous skin tumor formation. As the cyclin-dependent kinase inhibitor p21 regulates proliferation and differentiation in...


    pub_type: 杂志文章


    authors: Saiz-Ladera C,Lara MF,Garín M,Ruiz S,Santos M,Lorz C,García-Escudero R,Martínez-Fernández M,Bravo A,Fernández-Capetillo O,Segrelles C,Paramio JM

    更新日期:2014-09-11 00:00:00

  • MHC class I dysfunction of glioma stem cells escapes from CTL-mediated immune response via activation of Wnt/β-catenin signaling pathway.

    abstract::Glioma stem cells (GSCs) decrease T cells cognition and evade systemic immunosurveillance via downregulations or defects of major histocompatibility complex class I (MHC-I) molecule and antigen-processing machinery (APM) components. Improvement of tumor surface antigens of GSCs may be effective strategy to trigger an ...


    pub_type: 杂志文章


    authors: Yang W,Li Y,Gao R,Xiu Z,Sun T

    更新日期:2020-01-01 00:00:00

  • Type I interferon/IRF7 axis instigates chemotherapy-induced immunological dormancy in breast cancer.

    abstract::Neoadjuvant and adjuvant chemotherapies provide survival benefits to breast cancer patients, in particular in estrogen receptor negative (ER-) cancers, by reducing rates of recurrences. It is assumed that the benefits of (neo)adjuvant chemotherapy are due to the killing of disseminated, residual cancer cells, however,...


    pub_type: 杂志文章


    authors: Lan Q,Peyvandi S,Duffey N,Huang YT,Barras D,Held W,Richard F,Delorenzi M,Sotiriou C,Desmedt C,Lorusso G,Rüegg C

    更新日期:2019-04-01 00:00:00

  • hAda3 regulates p14ARF-induced p53 acetylation and senescence.

    abstract::Acetylation is thought to be a key event for p53 activation. We demonstrate that p14ARF-induced senescence of human mammary epithelial cells (MEC) is associated with p53 acetylation and requires hAda3, a component of histone acetyltransferase complexes and a p53 transcriptional coactivator. Expression of the N-termina...


    pub_type: 杂志文章


    authors: Sekaric P,Shamanin VA,Luo J,Androphy EJ

    更新日期:2007-09-20 00:00:00

  • Phorbol esters inhibit fibroblast growth factor-2-stimulated fibroblast proliferation by a p38 MAP kinase dependent pathway.

    abstract::Treatment of fibroblasts with the phorbol ester, 12-O-tetradecanoyl phorbol 13-acetate (TPA), specifically inhibits fibroblast growth factor-2 (FGF-2) induced proliferation. TPA treatment has little or no effect on FGF receptor activation but specifically inhibits the activation of p38 MAPK but not other downstream si...


    pub_type: 杂志文章


    authors: Maher P

    更新日期:2002-03-27 00:00:00

  • Discrimination between serous low malignant potential and invasive epithelial ovarian tumors using molecular profiling.

    abstract::Tumors of low malignant potential (LMP) represent 20% of epithelial ovarian cancers (EOCs) and are associated with a better prognosis than the invasive tumors (TOV). Defining the relationship between LMPs and TOVs remains an important goal towards understanding the molecular pathways that contribute to prognosis, as w...


    pub_type: 杂志文章


    authors: Ouellet V,Provencher DM,Maugard CM,Le Page C,Ren F,Lussier C,Novak J,Ge B,Hudson TJ,Tonin PN,Mes-Masson AM

    更新日期:2005-07-07 00:00:00

  • Isolation of a new class of 'flat' revertants from ras-transformed NIH3T3 cells using cis-4-hydroxy-L-proline.

    abstract::A new class of nontransformed revertant cells has been isolated from the ras-transformed cell line DT using cis-4-hydroxy-L-proline (CHP) as a selective agent. The new revertants, CHP 9CJ and CHP CB4, each contain two copies of the v-Ki-ras gene, elevated levels of phosphorylated p21ras protein, and rescuable transfor...


    pub_type: 杂志文章


    authors: Yanagihara K,Ciardiello F,Talbot N,McGeady ML,Cooper H,Benade L,Salomon DS,Bassin RH

    更新日期:1990-08-01 00:00:00

  • Signalling pathways leading to neuroblastoma differentiation after serum withdrawal: HDL blocks neuroblastoma differentiation by inhibition of EGFR.

    abstract::Neuroblastoma is the second most common pediatric malignancy, characterized by a high rate of unexplained spontaneous remissions. Much progress has been made in understanding neuroblastoma differentiation triggered by certain agents such as retinoic acid. However, little is known about the signalling pathways that lea...


    pub_type: 杂志文章


    authors: Evangelopoulos ME,Weis J,Krüttgen A

    更新日期:2005-05-05 00:00:00

  • Effect of glycogen synthase kinase-3 inactivation on mouse mammary gland development and oncogenesis.

    abstract::Many components of the Wnt/β-catenin signaling pathway have critical functions in mammary gland development and tumor formation, yet the contribution of glycogen synthase kinase-3 (GSK-3α and GSK-3β) to mammopoiesis and oncogenesis is unclear. Here, we report that WAP-Cre-mediated deletion of GSK-3 in the mammary epit...


    pub_type: 杂志文章


    authors: Dembowy J,Adissu HA,Liu JC,Zacksenhaus E,Woodgett JR

    更新日期:2015-07-01 00:00:00

  • Stat3-coordinated Lin-28-let-7-HMGA2 and miR-200-ZEB1 circuits initiate and maintain oncostatin M-driven epithelial-mesenchymal transition.

    abstract::Inflammation can act as a crucial mediator of epithelial-to-mesenchymal transition (EMT). In this study, we show that oncostatin M (OSM) is expressed in an autocrine/paracrine fashion in invasive breast carcinoma. OSM stimulation promotes spontaneous lung metastasis of MCF-7 xenografts in nude mice. A conspicuous epig...


    pub_type: 杂志文章


    authors: Guo L,Chen C,Shi M,Wang F,Chen X,Diao D,Hu M,Yu M,Qian L,Guo N

    更新日期:2013-11-07 00:00:00

  • CtBP promotes metastasis of breast cancer through repressing cholesterol and activating TGF-β signaling.

    abstract::Metastasis is the process through which the primary cancer cells spread beyond the primary tumor and disseminate to other organs. Most cancer patients die of metastatic disease. EMT is proposed to be the initial event associated with cancer metastasis and how it occurred is still a mystery. CtBP is known as a co-repre...


    pub_type: 杂志文章


    authors: Zhao Z,Hao D,Wang L,Li J,Meng Y,Li P,Wang Y,Zhang C,Zhou H,Gardner K,Di LJ

    更新日期:2019-03-01 00:00:00

  • Inhibition of CD4/p56lck signaling by a dominant negative mutant of the Shc adaptor protein.

    abstract::T-cell antigen receptor stimulation results in phosphorylation of the SH2 containing Shc proteins and recruitment of the Grb2/mSos complex suggesting that Shc proteins are involved in transducing T-cell activating signals to Ras. We have measured the effects of the isolated Shc-SH2 domain and the dominant negative Ras...


    pub_type: 杂志文章


    authors: Baldari CT,Pelicci G,Di Somma MM,Milia E,Giuli S,Pelicci PG,Telford JL

    更新日期:1995-03-16 00:00:00

  • Rap1A protein interferes with various MAP kinase activating pathways in skeletal myogenic cells.

    abstract::Constitutive expression of the activated Rap1A protein inhibits differentiation of myogenic C2 cells whereas the inactivated Rap1A protein favours cell differentiation and induces late endocytic compartments clustering. Although the role of Rap1A in MAPK activation has been analysed in various cell types, the signalli...


    pub_type: 杂志文章


    authors: Pizon V,Baldacci G

    更新日期:2000-12-07 00:00:00

  • Transformation of Madin-Darby canine kidney (MDCK) epithelial cells by Epstein-Barr virus latent membrane protein 1 (LMP1) induces expression of Ets1 and invasive growth.

    abstract::The Epstein-Barr virus (EBV)-encoded latent membrane protein 1 (LMP1) has a significant role in initiating EBV-associated lymphoproliferative disease and EBV-related malignancies. In view of clinical features related to the type of EBV latency, LMP1 may influence invasiveness of EBV associated tumors categorized as ty...


    pub_type: 杂志文章


    authors: Kim KR,Yoshizaki T,Miyamori H,Hasegawa K,Horikawa T,Furukawa M,Harada S,Seiki M,Sato H

    更新日期:2000-03-30 00:00:00

  • Prognostic significance of allelic losses in primary melanoma.

    abstract::Loss of genetic material, including loss of loci on chromosome arms 6q, 9p, and 10q, occurs frequently in cutaneous melanoma but infrequently in benign melanocytic nevi or other melanocytic lesions, suggesting that these genetic alterations are important in the development and progression of melanoma. To examine wheth...


    pub_type: 杂志文章


    authors: Healy E,Belgaid C,Takata M,Harrison D,Zhu NW,Burd DA,Rigby HS,Matthews JN,Rees JL

    更新日期:1998-04-30 00:00:00

  • Chromosomal imbalances in human lung cancer.

    abstract::A wealth of cytogenetic data has demonstrated that numerous somatic genetic changes are involved in the pathogenesis of human lung cancer. Despite the complexity of the genomic changes observed in these neoplasms, recurrent chromosomal patterns have emerged. In this review, we summarize chromosomal alterations identif...


    pub_type: 杂志文章,评审


    authors: Balsara BR,Testa JR

    更新日期:2002-10-07 00:00:00

  • Characterization of p73 functional domains necessary for transactivation and growth suppression.

    abstract::p73, a p53 family member, is highly similar to p53 in both structure and function. Like p53, the p73 protein contains an N-terminal activation domain, a DNA-binding domain, a tetramerization domain, and several PXXP motifs. Previously, we and others have shown that some functional domains in p53, such as the DNA-bindi...


    pub_type: 杂志文章


    authors: Nozell S,Wu Y,McNaughton K,Liu G,Willis A,Paik JC,Chen X

    更新日期:2003-07-10 00:00:00

  • Glycolysis gatekeeper PDK1 reprograms breast cancer stem cells under hypoxia.

    abstract::Glycolysis is critical for cancer stem cell reprogramming; however, the underlying regulatory mechanisms remain elusive. Here, we show that pyruvate dehydrogenase kinase 1 (PDK1) is enriched in breast cancer stem cells (BCSCs), whereas depletion of PDK1 remarkably diminishes ALDH+ subpopulations, decreases stemness-re...


    pub_type: 杂志文章


    authors: Peng F,Wang JH,Fan WJ,Meng YT,Li MM,Li TT,Cui B,Wang HF,Zhao Y,An F,Guo T,Liu XF,Zhang L,Lv L,Lv DK,Xu LZ,Xie JJ,Lin WX,Lam EW,Xu J,Liu Q

    更新日期:2018-02-22 00:00:00

  • Modulation of PKM alternative splicing by PTBP1 promotes gemcitabine resistance in pancreatic cancer cells.

    abstract::Pancreatic ductal adenocarcinoma (PDAC) is an aggressive and incurable disease. Poor prognosis is due to multiple reasons, including acquisition of resistance to gemcitabine, the first-line chemotherapeutic approach. Thus, there is a strong need for novel therapies, targeting more directly the molecular aberrations of...


    pub_type: 杂志文章


    authors: Calabretta S,Bielli P,Passacantilli I,Pilozzi E,Fendrich V,Capurso G,Fave GD,Sette C

    更新日期:2016-04-21 00:00:00

  • Constitutive activation of Stat3 by the Src and JAK tyrosine kinases participates in growth regulation of human breast carcinoma cells.

    abstract::Constitutive activation of signal transducer and activator of transcription (STAT) proteins has been detected in a wide variety of human primary tumor specimens and tumor cell lines including blood malignancies, head and neck cancer, and breast cancer. We have previously demonstrated a high frequency of Stat3 DNA-bind...


    pub_type: 杂志文章


    authors: Garcia R,Bowman TL,Niu G,Yu H,Minton S,Muro-Cacho CA,Cox CE,Falcone R,Fairclough R,Parsons S,Laudano A,Gazit A,Levitzki A,Kraker A,Jove R

    更新日期:2001-05-03 00:00:00

  • The role of Tcfap2c in tumorigenesis and cancer growth in an activated Neu model of mammary carcinogenesis.

    abstract::TFAP2C/AP-2γ influences development of the mammary gland and regulates patterns of gene expression in luminal and HER2-amplified breast cancer. The roles of TFAP2C in mammary gland tumorigenesis and in pathways critical to cancer progression remain poorly understood. To gain greater insight into oncogenic mechanisms r...


    pub_type: 杂志文章


    authors: Park JM,Wu T,Cyr AR,Woodfield GW,De Andrade JP,Spanheimer PM,Li T,Sugg SL,Lal G,Domann FE,Zhang W,Weigel RJ

    更新日期:2015-12-10 00:00:00

  • Cellular ITAM-containing proteins are oncoproteins in nonhematopoietic cells.

    abstract::Immunoreceptor tyrosine-based activation motifs (ITAMs) are involved in the transduction of signals necessary for activation, differentiation, and survival in hematopoietic cells. Several viruses have been shown to encode ITAM-containing transmembrane proteins. Although expression of these viral proteins has in some c...


    pub_type: 杂志文章


    authors: Grande SM,Katz E,Crowley JE,Bernardini MS,Ross SR,Monroe JG

    更新日期:2006-05-04 00:00:00

  • The human papillomavirus type 16 (HPV-16) E5 protein sensitizes human keratinocytes to apoptosis induced by osmotic stress.

    abstract::We have studied the role of the HPV-16 E5 protein in apoptosis, using HaCaT cell lines stably transfected with either E5 (HaCaT/E5) or the empty vector (HaCaT/pMSG) as control. When subjected to a hyperosmolar concentration of sorbitol, HaCaT/E5 cells respond with cytochrome c release, activation of caspase-3, -8, and...


    pub_type: 杂志文章


    authors: Kabsch K,Alonso A

    更新日期:2002-01-31 00:00:00

  • Combined effects of the two reciprocal t(4;11) fusion proteins MLL.AF4 and AF4.MLL confer resistance to apoptosis, cell cycling capacity and growth transformation.

    abstract::The reciprocal chromosomal translocation t(4;11) is correlated with infant, childhood, adult and therapy-related high-risk acute leukemia. Here, we investigated the biological effects of MLL.AF4, AF4.MLL or the combination of both reciprocal fusion proteins in a conditional in vitro cell culture model system. Several ...


    pub_type: 杂志文章


    authors: Gaussmann A,Wenger T,Eberle I,Bursen A,Bracharz S,Herr I,Dingermann T,Marschalek R

    更新日期:2007-05-17 00:00:00

  • AMD1 is required for the maintenance of leukemic stem cells and promotes chronic myeloid leukemic growth.

    abstract::Polyamines are critical elements in mammals, but it remains unknown whether adenosyl methionine decarboxylase (AMD1), a rate-limiting enzyme in polyamine synthesis, is required for myeloid leukemia. Here, we found that leukemic stem cells (LSCs) were highly differentiated, and leukemia progression was severely impaire...


    pub_type: 杂志文章


    authors: Sari IN,Yang YG,Wijaya YT,Jun N,Lee S,Kim KS,Bajaj J,Oehler VG,Kim SH,Choi SY,Park SH,Kim DW,Reya T,Han J,Kwon HY

    更新日期:2021-01-01 00:00:00

  • Cisplatin treatment increases survival and expansion of a highly tumorigenic side-population fraction by upregulating VEGF/Flt1 autocrine signaling.

    abstract::The cellular and molecular mechanisms of tumor progression following chemotherapy are largely unknown. Here, we demonstrate that cisplatin (CDDP) treatment upregulates VEGF and Flt1 expression leading to the survival and expansion of a highly tumorigenic fraction of side-population (SP) cells in osteosarcoma (HOS), ne...


    pub_type: 杂志文章


    authors: Tsuchida R,Das B,Yeger H,Koren G,Shibuya M,Thorner PS,Baruchel S,Malkin D

    更新日期:2008-06-26 00:00:00

  • Hyperplasia, hyperkeratosis and benign tumor production in transgenic mice by a targeted v-fos oncogene suggest a role for fos in epidermal differentiation and neoplasia.

    abstract::A vector, derived from the human K1 keratin gene, has been employed to target v-fos expression exclusively in the epidermis of transgenic mice. Adult transgenic mice expressors (3-4 months) displayed hyperplasia and hyperkeratosis, initially in wounded (tagged) ears, which later became bilateral. This phenotype appear...


    pub_type: 杂志文章


    authors: Greenhalgh DA,Rothnagel JA,Wang XJ,Quintanilla MI,Orengo CC,Gagne TA,Bundman DS,Longley MA,Fisher C,Roop DR

    更新日期:1993-08-01 00:00:00