Targeting RNA Polymerase I With Hernandonine Inhibits Ribosomal RNA Synthesis And Tumor Cell Growth
Yenting Chen, Jih-Jung Chen, Hsiang-Tsui Wang
Published 2019 · Biology, Medicine
Download PDFAnalyze on Scholarcy
RNA polymerase I (RNA Pol. I) activity is consistently expanded in multiplying cells to continue the expanded interest for ribosome generation and protein synthesis, which are fundamental for cell development and division. Thus, selective inhibitors of RNA Pol. I may offer a general helpful intends to block cancer cell multiplication. Hernandonine, isolated from the root wood of Hernandia nymphaeifolia, causes rearrangement of nucleolar proteins consistent with segregation of the nucleolus, a hallmark of RNA Pol. I transcription stress. Furthermore, the compound destabilizes RPA194, the large catalytic protein of RNA Pol. I, in a proteasome-dependent manner and inhibits nascent rRNA synthesis and expression of the 45S rRNA precursor. Finally, hernandonine induces cellular apoptosis through a p53-dependent or p53-independent process in solid tumor cell lines. These outcomes feature the prevailing effect of RNA Pol. I transcription stress on apoptosis pathway initiation and present a synthetically novel and significant molecule that represses RNA Pol. I, making it a potential objective for malignancy treatment. Implications: Our findings position hernandonine as a potential, particular, and orally administered cancer treatment agent appropriate for use in investigational clinical trials.
This paper references
The Nucleolus under Stress
Séverine Boulon (2010)
Cell cycle control across the eukaryotic kingdom.
Hirofumi Harashima (2013)
Awakening guardian angels: drugging the p53 pathway
Christopher J. Brown (2009)
The RNA polymerase I transcription machinery: an emerging target for the treatment of cancer.
Denis Drygin (2010)
Stabilization of E2F1 protein by MDM2 through the E2F1 ubiquitination pathway
Z. Zhang (2005)
MYC as a regulator of ribosome biogenesis and protein synthesis
Jan van Riggelen (2010)
Growth control and ribosome biogenesis.
Harri Lempiäinen (2009)
DNA damage-induced downregulation of human Cdc25C and Cdc2 is mediated by cooperation between p53 and maintenance DNA (cytosine-5) methyltransferase
G Le Gac (2006)
Direct p53 Transcriptional Repression: In Vivo Analysis of CCAAT-Containing G2/M Promoters
C. Imbriano (2005)
The Dual Specificity Phosphatase Cdc25C is a Direct Target for Transcriptional Repression by the Tumor Suppressor p53
S. S. Clair (2006)
Effect of Carcinogenic Acrolein on DNA Repair and Mutagenic Susceptibility*
Hsiang-Tsui Wang (2012)
New aporphine alkaloids and cytotoxic constituents of Hernandia nymphaeifolia.
I. S. Chen (1997)
Chemotherapy and the war on cancer
Bruce A. Chabner (2005)
Timeline: chemotherapy and thewar on cancer
BA Chabner (2005)
Nucleolar Adaptation in Human Cancer
L. Maggi (2005)
DNA Damage-induced Down-regulation of Human Cdc25C and Cdc2 Is Mediated by Cooperation between p53 and Maintenance DNA (Cytosine-5) Methyltransferase 1*
G. Gac (2006)
Cdc25 protein phosphatases in cell proliferation.
Giulio F. Draetta (1997)
Inhibiting eukaryotic transcription. Which compound to choose? How to evaluate its activity?
Olivier Bensaude (2011)
Small Molecule BMH-Compounds That Inhibit RNA Polymerase I and Cause Nucleolar Stress
K Peltonen (2014)
Quantitative Proteomics and Dynamic Imaging of the Nucleolus Reveal Distinct Responses to UV and Ionizing Radiation*
Henna M. Moore (2011)
Natural products in cancer chemotherapy: past, present and future
J. Mann (2002)
Bcl-2 is the target of a UV-inducible apoptosis switch and a node for UV signaling
D. Knezevic (2007)
Acrolein induced DNA damage, mutagenicity and effect on DNA repair.
M. Tang (2011)
Targeting RNA polymerase I with an oral small molecule CX-5461 inhibits ribosomal RNA synthesis and solid tumor growth.
D. Drygin (2011)
Essential role of ribosomal protein L11 in mediating growth inhibition-induced p53 activation.
K. Bhat (2004)
Acrolein preferentially damages nucleolus eliciting ribosomal stress and apoptosis in human cancer cells
Hsiang-Tsui Wang (2016)
Design, synthesis and anticancer activity of oxoaporphine alkaloid derivatives
Yong-Biao Wei (2014)
The nucleolus—guardian of cellular homeostasis and genome integrity
Ingrid Grummt (2013)
Does the ribosome translate cancer?
D. Ruggero (2003)
Anticancer activity of CX-3543: a direct inhibitor of rRNA biogenesis.
Denis Drygin (2009)
Translational control in cancer
Deborah Silvera (2010)
Alkaloids from hernandia sonora phytochem-istry1995
RNA polymerases I and III, growth control and cancer
R. White (2005)
臺灣藥用植物誌 = Manual of medicinal plants in Taiwan
甘 偉松 (1975)
The multifunctional nucleolus
F. Boisvert (2007)
Regulating the p53 pathway: in vitro hypotheses, in vivo veritas
F. Toledo (2006)
Nucleolar stress with and without p53
Allison James (2014)
Inhibition of HDM2 and Activation of p53 by Ribosomal Protein L23
Aiwen Jin (2004)
Cell death mechanisms of plant-derived anticancer drugs: beyond apoptosis
Hala Gali-Muhtasib (2015)
miR-134 targets PDCD7 to reduce E-cadherin expression and enhance oral cancer progression.
Shih-Yuan Peng (2018)
Inhibition of MDM2-mediated p53 Ubiquitination and Degradation by Ribosomal Protein L5*
M. Dai (2004)
New dimeric aporphine alkaloids and cytotoxic constituents of Hernandia nymphaeifolia.
Jih-Jung Chen (1996)
Selective inhibition of rRNA transcription downregulates E2F-1: a new p53-independent mechanism linking cell growth to cell proliferation
G. Donati (2011)
The nucleolus: an old factory with unexpected capabilities.
M. Olson (2000)
Actinomycin and DNA transcription.
H. Sobell (1985)
Alkaloids from hernandia sonora phytochemistry1995;40:983–6
ISC Chen (1995)
PUMA, a novel proapoptotic gene, is induced by p53.
K. Nakano (2001)
Targeting RNA polymerase I transcription and the nucleolus for cancer therapy
R. Hannan (2013)
Different effects of ribosome biogenesis inhibition on cell proliferation in retinoblastoma protein- and p53-deficient and proficient human osteosarcoma cell lines.
L. Montanaro (2007)
Dynamic sorting of nuclear components into distinct nucleolar caps during transcriptional inhibition.
Y. Shav-Tal (2005)
Chemotherapeutic Drugs Inhibit Ribosome Biogenesis at Various Levels*
Kaspar Burger (2010)
Extracellular Matrix Composition and Remodeling in Human Abdominal Aortic Aneurysms: A Proteomics Approach*
Athanasios Didangelos (2011)
p53 -Dependent and -Independent Nucleolar Stress Responses
Karl Holmberg Olausson (2012)
A targeting modality for destruction of RNA polymerase I that possesses anticancer activity.
K Peltonen (2014)
DNA damage-induced downregulation of Cdc25C is mediated by p53 via two independent mechanisms: one involves direct binding to the cdc25C promoter.
S. St Clair (2004)
This paper is referenced by
The p53 family reaches the final frontier: the variegated regulation of the dark matter of the genome by the p53 family in cancer.
Marco Napoli (2020)