Small molecule inhibitors of IRES-mediated translation.

Abstract:

:Many genes controlling cell proliferation and survival (those most important to cancer biology) are now known to be regulated specifically at the translational (RNA to protein) level. The internal ribosome entry site (IRES) provides a mechanism by which the translational efficiency of an individual or group of mRNAs can be regulated independently of the global controls on general protein synthesis. IRES-mediated translation has been implicated as a significant contributor to the malignant phenotype and chemoresistance, however there has been no effective means by which to interfere with this specialized mode of protein synthesis. A cell-based empirical high-throughput screen was performed in attempt to identify compounds capable of selectively inhibiting translation mediated through the IGF1R IRES. Results obtained using the bicistronic reporter system demonstrate selective inhibition of second cistron translation (IRES-dependent). The lead compound and its structural analogs completely block de novo IGF1R protein synthesis in genetically-unmodified cells, confirming activity against the endogenous IRES. Spectrum of activity extends beyond IGF1R to include the c-myc IRES. The small molecule IRES inhibitor differentially modulates synthesis of the oncogenic (p64) and growth-inhibitory (p67) isoforms of Myc, suggesting that the IRES controls not only translational efficiency, but also choice of initiation codon. Sustained IRES inhibition has profound, detrimental effects on human tumor cells, inducing massive (>99%) cell death and complete loss of clonogenic survival in models of triple-negative breast cancer. The results begin to reveal new insights into the inherent complexity of gene-specific translational regulation, and the importance of IRES-mediated translation to tumor cell biology.

journal_name

Cancer Biol Ther

journal_title

Cancer biology & therapy

authors

Vaklavas C,Meng Z,Choi H,Grizzle WE,Zinn KR,Blume SW

doi

10.1080/15384047.2015.1071729

subject

Has Abstract

pub_date

2015-01-01 00:00:00

pages

1471-85

issue

10

eissn

1538-4047

issn

1555-8576

journal_volume

16

pub_type

杂志文章
  • Mitogen-activated protein kinase phosphatase-1 inhibition and sustained extracellular signal-regulated kinase 1/2 activation in camptothecin-induced human colon cancer cell death.

    abstract::Camptothecins are commonly used chemotherapeutics; in some models, they enhance signaling via the mitogen-activated protein kinase (MAPK) pathway through effects on upstream kinases. To evaluate the impact of camptothecin (CPT) on MAPKs in human colon cancer, we studied HCT116 and CaCo2 colon cancer cells. We found th...

    journal_title:Cancer biology & therapy

    pub_type: 杂志文章

    doi:10.4161/cbt.26044

    authors: Lee M,Young Kim S,Kim J,Kim HS,Kim SM,Kim EJ

    更新日期:2013-11-01 00:00:00

  • Pancreatic and bile duct cancer circulating tumor cells (CTC) form immune-resistant multi-cell type clusters in the portal venous circulation.

    abstract::Circulating tumor cells (CTC) enter the blood from many carcinomas and represent a likely source of metastatic dissemination. In contrast to the peripheral circulation, KRAS mutation- positive CTC thrive in the portal venous blood of patients with pancreatic ductal adenocarcinoma (PDAC). To analyze the essential inter...

    journal_title:Cancer biology & therapy

    pub_type: 杂志文章

    doi:10.1080/15384047.2018.1480292

    authors: Arnoletti JP,Fanaian N,Reza J,Sause R,Almodovar AJ,Srivastava M,Patel S,Veldhuis PP,Griffith E,Shao YP,Zhu X,Litherland SA

    更新日期:2018-01-01 00:00:00

  • A DNA repeat, NBL2, is hypermethylated in some cancers but hypomethylated in others.

    abstract::Hypermethylation at certain CpG-rich promoters and hypomethylation at repeated DNA sequences are very frequently found in cancers. We provide the first report that a DNA sequence (NBL2) can be either extensively hypermethylated or hypomethylated in cancer. Previously, it was shown that NBL2, a complex tandem DNA repea...

    journal_title:Cancer biology & therapy

    pub_type: 杂志文章

    doi:10.4161/cbt.4.4.1622

    authors: Nishiyama R,Qi L,Tsumagari K,Weissbecker K,Dubeau L,Champagne M,Sikka S,Nagai H,Ehrlich M

    更新日期:2005-04-01 00:00:00

  • The irreversible ERBB1/2/4 inhibitor neratinib interacts with the PARP1 inhibitor niraparib to kill ovarian cancer cells.

    abstract::The irreversible ERBB1/2/4 inhibitor neratinib has been shown to rapidly down-regulate the expression of ERBB1/2/4 as well as the levels of c-MET, PDGFRα and mutant RAS proteins via autophagic degradation. Neratinib interacted in an additive to synergistic fashion with the approved PARP1 inhibitor niraparib to kill ov...

    journal_title:Cancer biology & therapy

    pub_type: 杂志文章

    doi:10.1080/15384047.2018.1436024

    authors: Booth L,Roberts JL,Samuel P,Avogadri-Connors F,Cutler RE,Lalani AS,Poklepovic A,Dent P

    更新日期:2018-06-03 00:00:00

  • Somatostatin receptor scintigraphy screening in advanced hepatocarcinoma: A multi-center French study.

    abstract:BACKGROUND:Somatostatin receptor scintigraphy (SRS) has been reported for receptor (SSTR) screening in advanced hepatocarcinoma (aHC) prior to somatostatin analogue treatment. AIMS:To evaluate SSTR screening with SRS in aHC patients. RESULTS:Seventy aHC patients (63 men) aged 65 +/- 11 y were included, with alcohol, ...

    journal_title:Cancer biology & therapy

    pub_type: 杂志文章,多中心研究

    doi:10.4161/cbt.8.21.9737

    authors: Nguyen-Khac E,Ollivier I,Aparicio T,Moullart V,Hugentobler A,Lebtahi R,Lobry C,Susini C,Duhamel C,Hommel S,Cadranel JF,Joly JP,Barbare JC,Tramier B,Dupas JL

    更新日期:2009-11-01 00:00:00

  • Proteomic profiling: a novel method for differential diagnosis?

    abstract::Tumors with identical phenotype can have markedly different biologic behavior. The differentiation between hemangioblastoma, a benign vascular brain tumor, and renal cell carcinoma (RCC), a malignant tumor that can metastasize to the brain, is a well-known pathological quandary. We report a 59-year-old female with von...

    journal_title:Cancer biology & therapy

    pub_type: 杂志文章

    doi:10.4161/cbt.6.3.3673

    authors: Gläsker S,Lonser RR,Okamoto H,Li J,Jaffee H,Oldfield EH,Zhuang Z,Vortmeyer AO

    更新日期:2007-03-01 00:00:00

  • Cross-talk of WNT and FGF signaling pathways at GSK3beta to regulate beta-catenin and SNAIL signaling cascades.

    abstract::WNT and FGF signaling pathways cross-talk during a variety of cellular processes, such as human colorectal carcinogenesis, mouse mammary tumor virus (MMTV)-induced carcinogenesis, E2A-Pbx-induced leukemogenesis, early embryogenesis, body-axis formation, limb-bud formation, and neurogenesis. Canonical WNT signals are t...

    journal_title:Cancer biology & therapy

    pub_type: 杂志文章,评审

    doi:10.4161/cbt.5.9.3151

    authors: Katoh M,Katoh M

    更新日期:2006-09-01 00:00:00

  • Functional characterization of NAD dependent de-acetylases SIRT1 and SIRT2 in B-Cell Chronic Lymphocytic Leukemia (CLL).

    abstract::Sirtuins (SIRT) are nicotinamide adenine dinucleotide (NAD+) dependent deacetylases or ADP- ribosyl transferases (ARTs) that deacetylate lysine residues on various proteins regulating a variety of cellular and metabolic processes. These enzymes regulate metabolism, cell survival, differentiation and DNA repair. SIRT p...

    journal_title:Cancer biology & therapy

    pub_type: 杂志文章

    doi:10.1080/15384047.2016.1139246

    authors: Bhalla S,Gordon LI

    更新日期:2016-01-01 00:00:00

  • Effects of Streptococcus thermophilus TH-4 on intestinal mucositis induced by the chemotherapeutic agent, 5-Fluorouracil (5-FU).

    abstract::Beneficial bacteria (probiotics) and probiotic-derived factors have the potential to ameliorate disorders of the intestine. The aim of this study was to compare live Streptococcus thermophilus TH-4 (TH-4), dead TH-4 and TH-4 supernatant in rats treated with 5-Fluorouracil. Rats were randomly allocated to five treatmen...

    journal_title:Cancer biology & therapy

    pub_type: 杂志文章

    doi:

    authors: Whitford EJ,Cummins AG,Butler RN,Prisciandaro LD,Fauser JK,Yazbeck R,Lawrence A,Cheah KY,Wright TH,Lymn KA,Howarth GS

    更新日期:2009-03-15 00:00:00

  • Inhibition of MCL-1 in breast cancer cells promotes cell death in vitro and in vivo.

    abstract::The present studies have examined approaches to suppress MCL-1 function in breast cancer cells, as a means to promote tumor cell death. Treatment of breast cancer cells with CDK inhibitors (flavopiridol; roscovitine) enhanced the lethality of the ERBB1 inhibitor lapatinib in a synergistic fashion. CDK inhibitors inter...

    journal_title:Cancer biology & therapy

    pub_type: 杂志文章

    doi:10.4161/cbt.10.9.13273

    authors: Mitchell C,Yacoub A,Hossein H,Martin AP,Bareford MD,Eulitt P,Yang C,Nephew KP,Dent P

    更新日期:2010-11-01 00:00:00

  • Atorvastatin induces autophagy in prostate cancer PC3 cells through activation of LC3 transcription.

    abstract::Our previous studies have demonstrated that atorvastatin induces autophagy in the androgen receptor negative prostate cancer PC3 cells through inhibition of geranylgeranyl biosynthesis [Parikh et al., Prostate. 70(9): 971-981 (2010)]. This study attempts to elucidate the molecular mechanism underlying atorvastatin-ind...

    journal_title:Cancer biology & therapy

    pub_type: 杂志文章

    doi:10.4161/cbt.12.8.15978

    authors: Toepfer N,Childress C,Parikh A,Rukstalis D,Yang W

    更新日期:2011-10-15 00:00:00

  • Differential impact of fibroblasts on the efficient cell death of lung cancer cells induced by paclitaxel and cisplatin.

    abstract::The efficient treatment of lung carcinomas with chemotherapeutics still poses a challenge for anti-cancer therapy. Since stromal cells of the tumor may alter the responsiveness of tumor cells to chemotherapeutics, we studied the impact of lung fibroblasts (WI-38) on the chemotherapy-induced death of non-small cell lun...

    journal_title:Cancer biology & therapy

    pub_type: 杂志文章

    doi:10.4161/cbt.7.8.6264

    authors: Bartling B,Hofmann HS,Silber RE,Simm A

    更新日期:2008-08-01 00:00:00

  • Aggressive myeloid leukemia formation is directed by the Musashi 2/Numb pathway.

    abstract::Chronic myeloid leukemia (CML) progresses from a chronic phase to a deadly blast crisis phase. While it is known that BCR-ABL initiates the disease and that secondary molecular and genetic abnormalities likely contribute to progression of the disease to blast crisis, details regarding the mechanism(s) of blast phase p...

    journal_title:Cancer biology & therapy

    pub_type: 杂志文章

    doi:10.4161/cbt.10.10.14010

    authors: Griner LN,Reuther GW

    更新日期:2010-11-15 00:00:00

  • Upregulation of the androgen receptor during prostate cancer progression.

    abstract::The androgen receptor is one of the central factors in mediating prostate cancer progression and is an important target for treatment. Several possible mechanisms have been put forth as to how it promotes this process. In the January 2004 issue of Nature Medicine, Chen et al. report that the androgen receptor is consi...

    journal_title:Cancer biology & therapy

    pub_type: 杂志文章

    doi:10.4161/cbt.3.3.785

    authors: Singh A,Figg WD

    更新日期:2004-03-01 00:00:00

  • ETS-TMPRSS2 fusion gene products in prostate cancer.

    abstract::Genes playing a role in carcinogenesis have often been identified through analysis of recurrent chromosomal rearrangements. Although such rearrangements are well known in leukemias, lymphomas, and sarcomas, they have not been well characterized in carcinomas. In the October 28, 2005 issue of Science, a study by Tomlin...

    journal_title:Cancer biology & therapy

    pub_type: 杂志文章

    doi:10.4161/cbt.5.3.2603

    authors: Ahlers CM,Figg WD

    更新日期:2006-03-01 00:00:00

  • Efficacy of the dual PI3K and mTOR inhibitor NVP-BEZ235 in combination with nilotinib against BCR-ABL-positive leukemia cells involves the ABL kinase domain mutation.

    abstract::Imatinib, an ABL tyrosine kinase inhibitor (TKI), has shown clinical efficacy against chronic myeloid leukemia (CML). However, a substantial number of patients develop resistance to imatinib treatment due to the emergence of clones carrying mutations in the protein BCR-ABL. The phosphoinositide 3 kinase (PI3K)/Akt/mam...

    journal_title:Cancer biology & therapy

    pub_type: 杂志文章

    doi:10.4161/cbt.26725

    authors: Okabe S,Tauchi T,Tanaka Y,Kitahara T,Kimura S,Maekawa T,Ohyashiki K

    更新日期:2014-02-01 00:00:00

  • Lipoic acid inhibits cell proliferation of tumor cells in vitro and in vivo.

    abstract::Cancer cells convert glucose preferentially to lactate even in the presence of oxygen (aerobic glycolysis-Warburg effect). New concepts in cancer treatment aim at inhibition of aerobic glycolysis. Pyruvate dehydrogenase converts pyruvate to acetylCoA thus preventing lactate formation. Therefore, the aim of this study ...

    journal_title:Cancer biology & therapy

    pub_type: 杂志文章

    doi:10.4161/cbt.22003

    authors: Feuerecker B,Pirsig S,Seidl C,Aichler M,Feuchtinger A,Bruchelt G,Senekowitsch-Schmidtke R

    更新日期:2012-12-01 00:00:00

  • Silencing the intestinal GUCY2C tumor suppressor axis requires APC loss of heterozygosity.

    abstract::Most sporadic colorectal cancer reflects acquired mutations in the adenomatous polyposis coli (APC) tumor suppressor gene, while germline heterozygosity for mutant APC produces the autosomal dominant disorder Familial Adenomatous Polyposis (FAP) with a predisposition to colorectal cancer. In these syndromes, loss of h...

    journal_title:Cancer biology & therapy

    pub_type: 杂志文章

    doi:10.1080/15384047.2020.1779005

    authors: Pattison AM,Barton JR,Entezari AA,Zalewski A,Rappaport JA,Snook AE,Waldman SA

    更新日期:2020-09-01 00:00:00

  • Growth inhibitory effects of gastric cancer cells with an increase in S phase and alkaline phosphatase activity repression by aloe-emodin.

    abstract::Aloe-emodin is a novel active compound found in the root and rhizome of Rheum palmatum. To investigate the effects and mechanisms of aloe-emodin on human gastric cancer, MGC-803 cells were treated with 2.5, 5, 10, 20 and 40 microM aloe-emodin for 1-5 d. The results showed that aloe-emodin inhibited the growth of cance...

    journal_title:Cancer biology & therapy

    pub_type: 杂志文章

    doi:10.4161/cbt.6.1.3553

    authors: Guo J,Xiao B,Zhang S,Liu D,Liao Y,Sun Q

    更新日期:2007-01-01 00:00:00

  • Renal angiomyolipoma (AML) harboring a missense mutation of TSC2 with copy-neutral loss of heterozygosity (CN-LOH).

    abstract::Angiomyolipoma (AML) is classified as a perivascular epithelioid cell neoplasm, mostly occurring in the kidney. Twenty percent of patients with renal AML have tuberous sclerosis complex (TSC) caused by germline variation in the TSC1 or TSC2 gene. In this paper, we report the first case of renal AML harboring somatic m...

    journal_title:Cancer biology & therapy

    pub_type: 杂志文章

    doi:10.1080/15384047.2019.1702406

    authors: Idogawa M,Hida T,Tanaka T,Ohira N,Tange S,Sasaki Y,Uhara H,Masumori N,Tokino T,Natori H

    更新日期:2020-04-02 00:00:00

  • Downregulation of XIAP and induction of apoptosis by the synthetic cyclin-dependent kinase inhibitor GW8510 in non-small cell lung cancer cells.

    abstract::Small-molecule inhibitors of cyclin-dependent kinases (CDKs) are known to induce cell cycle arrest and apoptosis in certain cancer cells. In order to evaluate the antitumor activity of one such inhibitor, GW8510, against human lung cancers, we analyzed the effects of GW8510 on six nonsmall cell lung cancer (NSCLC) cel...

    journal_title:Cancer biology & therapy

    pub_type: 杂志文章

    doi:10.4161/cbt.5.2.2316

    authors: Dong F,Guo W,Zhang L,Wu S,Teraishi F,Davis JJ,Fang B

    更新日期:2006-02-01 00:00:00

  • Pyoluteorin derivatives induce Mcl-1 degradation and apoptosis in hematological cancer cells.

    abstract::Mcl-1, a pro-survival member of the Bcl-2 protein family, is an attractive target for cancer therapy. We have recently identified the natural product marinopyrrole A (maritoclax) as a novel small molecule Mcl-1 inhibitor. Here, we describe the structure-activity relationship study of pyoluteorin derivatives based on m...

    journal_title:Cancer biology & therapy

    pub_type: 杂志文章

    doi:10.4161/15384047.2014.972799

    authors: Doi K,Gowda K,Liu Q,Lin JM,Sung SS,Dower C,Claxton D,Loughran TP Jr,Amin S,Wang HG

    更新日期:2014-01-01 00:00:00

  • New paradigms for cancer drug discovery.

    abstract::Discovering drugs has never been an easy task. Traditionally, this task has exclusively been undertaken by large pharmaceutical companies that recovered their high research and development costs by selling expensive medications. Despite the huge amount of time and effort devoted towards drug discovery over the last de...

    journal_title:Cancer biology & therapy

    pub_type: 杂志文章,评审

    doi:10.4161/cbt.2.4.448

    authors: Sager JA,Lengauer C

    更新日期:2003-07-01 00:00:00

  • Furanodiene induces G2/M cell cycle arrest and apoptosis through MAPK signaling and mitochondria-caspase pathway in human hepatocellular carcinoma cells.

    abstract::Furanodiene (C15H20O), a pure compound isolated from Traditional Chinese medicine, Curcuma wenyujin, named Ezhu in Chinese, which structure was determined on the basis of NMR, MS and UV spectrum. In this study, we attempted to characterize in detail the signaling cascades resulted from furanodiene-induced apoptosis in...

    journal_title:Cancer biology & therapy

    pub_type: 杂志文章

    doi:10.4161/cbt.6.7.4317

    authors: Xiao Y,Yang FQ,Li SP,Gao JL,Hu G,Lao SC,Conceição EL,Fung KP,Wangl YT,Lee SM

    更新日期:2007-07-01 00:00:00

  • Emodin enhances cytotoxicity of chemotherapeutic drugs in prostate cancer cells: the mechanisms involve ROS-mediated suppression of multidrug resistance and hypoxia inducible factor-1.

    abstract::The intrinsic or acquired resistance to multiple drugs (MDR) of cancer cells remains one of the main obstacles for chemotherapy. Development of small molecule targeting to hypoxia inducible factor-1 (HIF-1) has been recently proposed as strategy for treatments of drug-resistant solid tumors. In the present study, emod...

    journal_title:Cancer biology & therapy

    pub_type: 杂志文章

    doi:10.4161/cbt.7.3.5457

    authors: Huang XZ,Wang J,Huang C,Chen YY,Shi GY,Hu QS,Yi J

    更新日期:2008-03-01 00:00:00

  • Microarray expression profiling of dysregulated long non-coding RNAs in triple-negative breast cancer.

    abstract::Triple-negative breast cancer (TNBC) represents a collection of malignant breast tumors that are often aggressive and have an increased risk of metastasis and relapse. Long non-coding RNAs are generally defined as RNA transcripts measuring 200 nucleotides or longer that do not encode for any protein. During the past d...

    journal_title:Cancer biology & therapy

    pub_type: 杂志文章

    doi:10.1080/15384047.2015.1040957

    authors: Chen C,Li Z,Yang Y,Xiang T,Song W,Liu S

    更新日期:2015-01-01 00:00:00

  • Tumor suppressor p53 status does not determine the differentiation-associated G₁ cell cycle arrest induced in leukemia cells by 1,25-dihydroxyvitamin D₃ and antioxidants.

    abstract::Vitamin D derivatives can induce differentiation of human acute myeloid leukemia (AML) cells. Here, we investigated if the G₁ cell cycle block associated with monocytic differentiation is modulated by the p53 status of the cells treated with 1,25D, alone or with plant antioxidants carnosic acid (C) or silibinin (S), a...

    journal_title:Cancer biology & therapy

    pub_type: 杂志文章

    doi:10.4161/cbt.10.4.12366

    authors: Thompson T,Danilenko M,Vassilev L,Studzinski GP

    更新日期:2010-08-15 00:00:00

  • Rapamycin enhances cetuximab cytotoxicity by inhibiting mTOR-mediated drug resistance in mesenchymal hepatoma cells.

    abstract::The synergistic effect of combined drug therapy provides an enhanced treatment for advanced liver cancer. We aimed to investigate the underlying mechanism of cetuximab sensitization by rapamycin in hepatoma cells. Four hepatoma cell lines, HepG2, HuH7, SNU-387, and SNU-449, were treated with cetuximab or cetuximab plu...

    journal_title:Cancer biology & therapy

    pub_type: 杂志文章

    doi:10.4161/cbt.29113

    authors: Chen W,Hu QD,Xia XF,Liang C,Liu H,Zhang Q,Ma T,Liang F,Liang TB

    更新日期:2014-08-01 00:00:00

  • mRNA expression profile of multidrug-resistant genes in acute lymphoblastic leukemia of children, a prognostic value for ABCA3 and ABCA2.

    abstract::Multidrug resistance (MDR) is an important cause of treatment failure in acute lymphoblastic leukemia (ALL). The ABC family of membrane transporters is proposed, albeit with controversy, to be involved in this process. The present study aims to investigate the mRNA expression profile of several genes of this family, i...

    journal_title:Cancer biology & therapy

    pub_type: 杂志文章

    doi:10.4161/cbt.26603

    authors: Rahgozar S,Moafi A,Abedi M,Entezar-E-Ghaem M,Moshtaghian J,Ghaedi K,Esmaeili A,Montazeri F

    更新日期:2014-01-01 00:00:00

  • BRCA1 phosphorylation: biological consequences.

    abstract::More than a decade has passed since BRCA1, breast cancer tumor suppressor 1, was isolated by reverse genetics in 1994. Its molecular structure and potential function have been extensively studied; both mouse genetics and a cell culture system revealed that BRCA1 is a 220,240 kD nuclear phosphoprotein, it regulates tra...

    journal_title:Cancer biology & therapy

    pub_type: 杂志文章,评审

    doi:10.4161/cbt.5.5.2845

    authors: Ouchi T

    更新日期:2006-05-01 00:00:00