scholarly journals SOD1 regulates ribosome biogenesis in KRAS mutant non-small cell lung cancer

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Xiaowen Wang ◽  
Hong Zhang ◽  
Russell Sapio ◽  
Jun Yang ◽  
Justin Wong ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Ribosome Biogenesis ◽  
Ribosomal Subunit ◽  
Tumor Burden ◽  
Cancer Cell Proliferation ◽  
Lung Cancer Cell ◽  
Ribosomal Subunits

AbstractSOD1 is known as the major cytoplasmic superoxide dismutase and an anticancer target. However, the role of SOD1 in cancer is not fully understood. Herein we describe the generation of an inducible Sod1 knockout in KRAS-driven NSCLC mouse model. Sod1 knockout markedly reduces tumor burden in vivo and blocks growth of KRAS mutant NSCLC cells in vitro. Intriguingly, SOD1 is enriched in the nucleus and notably in the nucleolus of NSCLC cells. The nuclear and nucleolar, not cytoplasmic, form of SOD1 is essential for lung cancer cell proliferation. Moreover, SOD1 interacts with PeBoW complex and controls its assembly necessary for pre-60S ribosomal subunit maturation. Mechanistically, SOD1 regulates co-localization of PeBoW with and processing of pre-rRNA, and maturation of cytoplasmic 60S ribosomal subunits in KRAS mutant lung cancer cells. Collectively, our study unravels a nuclear SOD1 function essential for ribosome biogenesis and proliferation in KRAS-driven lung cancer.

scholarly journals Critical Role of Gα12 and Gα13 for Human Small Cell Lung Cancer Cell Proliferation In vitro and Tumor Growth In vivo

2010 ◽  
Vol 16 (5) ◽  
pp. 1402-1415 ◽  
Author(s):  
Marius Grzelinski ◽  
Olaf Pinkenburg ◽  
Thomas Büch ◽  
Maike Gold ◽  
Stefanie Stohr ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Critical Role ◽  
Small Cell ◽  
Cancer Cell Proliferation ◽  
Lung Cancer Cell ◽  
Small Cell Lung ◽  
Proliferation In Vitro

scholarly journals Bauhinia acuminata L. attenuates lung cancer cell proliferation: in vitro, in vivo and in silico approaches

2021 ◽  
pp. 100173
Author(s):  
Divya Sebastian ◽  
K. Gowrishankar ◽  
S. Ignacimuthu ◽  
A.J. Renilda Sophy ◽  
R. Vidhya ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Cell Proliferation ◽  
Cancer Cell ◽  
In Silico ◽  
Cancer Cell Proliferation ◽  
Lung Cancer Cell ◽  
Proliferation In Vitro

scholarly journals Xenopus LSm Proteins Bind U8 snoRNA via an Internal Evolutionarily Conserved Octamer Sequence

2002 ◽  
Vol 22 (12) ◽  
pp. 4101-4112 ◽  
Author(s):  
Nenad Tomasevic ◽  
Brenda A. Peculis
Keyword(s):  
Ribosome Biogenesis ◽  
Rna Binding ◽  
Ribosomal Subunit ◽  
High Specificity ◽  
Sm Proteins ◽  
U6 Snrna ◽  
Evolutionarily Conserved

ABSTRACT U8 snoRNA plays a unique role in ribosome biogenesis: it is the only snoRNA essential for maturation of the large ribosomal subunit RNAs, 5.8S and 28S. To learn the mechanisms behind the in vivo role of U8 snoRNA, we have purified to near homogeneity and characterized a set of proteins responsible for the formation of a specific U8 RNA-binding complex. This 75-kDa complex is stable in the absence of added RNA and binds U8 with high specificity, requiring the conserved octamer sequence present in all U8 homologues. At least two proteins in this complex can be cross-linked directly to U8 RNA. We have identified the proteins as Xenopus homologues of the LSm (like Sm) proteins, which were previously reported to be involved in cytoplasmic degradation of mRNA and nuclear stabilization of U6 snRNA. We have identified LSm2, -3, -4, -6, -7, and -8 in our purified complex and found that this complex associates with U8 RNA in vivo. This purified complex can bind U6 snRNA in vitro but does not bind U3 or U14 snoRNA in vitro, demonstrating that the LSm complex specifically recognizes U8 RNA.

scholarly journals D -Glucuronyl C5-epimerase suppresses small-cell lung cancer cell proliferation in vitro and tumour growth in vivo

2011 ◽  
Vol 105 (1) ◽  
pp. 74-82 ◽  
Author(s):  
E V Grigorieva ◽  
T Y Prudnikova ◽  
N V Domanitskaya ◽  
L A Mostovich ◽  
T V Pavlova ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Cell Proliferation ◽  
Tumour Growth ◽  
Small Cell ◽  
Cancer Cell Proliferation ◽  
Lung Cancer Cell ◽  
Small Cell Lung ◽  
Proliferation In Vitro

scholarly journals RNA-binding protein KHSRP promotes tumor growth and metastasis in non-small cell lung cancer

2019 ◽  
Vol 38 (1) ◽  
Author(s):  
Mingxia Yan ◽  
Lei Sun ◽  
Jing Li ◽  
Huajian Yu ◽  
Hechun Lin ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Cancer Cell ◽  
Human Lung ◽  
Human Lung Cancer ◽  
Migration And Invasion ◽  
Cancer Cell Proliferation ◽  
Lung Cancer Cell ◽  
Small Cell Lung

Abstract Background KH-type splicing regulatory protein (KHSRP) plays an important role in cancer invasion, but the relevant mechanism is not well known. In the present study, we investigated the function and potential molecular mechanism of KHSRP in non-small cell lung cancer (NSCLC) metastasis and elucidated its clinical significance. Methods Isobaric tags for relative and absolute quantitation and the SWATH™ approach were combined with nanoliquid chromatography-tandem mass spectrometry analysis to identify metastasis-associated nucleoproteins in NSCLC. Real-time PCR and Western blot were used to screen for metastasis-associated candidate molecules. Gene knockdown and overexpression were used to investigate their functions and molecular mechanisms in lung cancer cells. Coimmunoprecipitation (Co-IP) experiments were performed to identify the interactions between candidate molecules and their interacting proteins. Gene expression and its association with multiple clinicopathologic characteristics were analyzed by immunohistochemistry (IHC) and Western blot in human lung cancer specimens. Results KHSRP was identified as a metastasis-associated candidate molecule. In NSCLC cell lines, knockdown of KHSRP significantly reduced lung cancer cell proliferation, migration, and invasion in vitro and in vivo, whereas overexpression of KHSRP did the opposite. Mechanistically, the protein heterogeneous nuclear ribonucleoprotein C (C1/C2) (HNRNPC) was identified to interact with KHSRP using Co-IP experiments. In NSCLC cell lines, overexpression of HNRNPC significantly promoted lung cancer cell proliferation, migration, and invasion in vitro and in vivo. KHSRP and HNRNPC may induce human lung cancer cell invasion and metastasis by activating the IFN-α-JAK-STAT1 signaling pathway. Drastically higher expression levels of KHSRP and HNRNPC were observed in lung cancer tissues compared to those in adjacent noncancerous tissues. Increased KHSRP and HNRNPC expression was significantly associated with advanced tumor stages and metastasis (both lymph node and distant). Kaplan-Meier survival analysis showed that patients with high KHSRP and HNRNPC expression levels were predicted to have the shortest survival times and to have a poor prognosis. Conclusions KHSRP plays an important role in NSCLC metastasis and may serve as a potential prognostic marker and novel therapeutic target for lung cancer metastasis treatment.

scholarly journals Structural basis of GTPase-mediated mitochondrial ribosome biogenesis and recycling

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Hauke S. Hillen ◽  
Elena Lavdovskaia ◽  
Franziska Nadler ◽  
Elisa Hanitsch ◽  
Andreas Linden ◽  
...  
Keyword(s):  
Ribosomal Proteins ◽  
Ribosome Biogenesis ◽  
Ribosomal Subunit ◽  
Structural Basis ◽  
Peptidyl Transferase ◽  
Mitochondrial Ribosomes ◽  
Mitochondrial Ribosome ◽  
In Vitro Reconstitution

AbstractRibosome biogenesis requires auxiliary factors to promote folding and assembly of ribosomal proteins and RNA. Particularly, maturation of the peptidyl transferase center (PTC) is mediated by conserved GTPases, but the molecular basis is poorly understood. Here, we define the mechanism of GTPase-driven maturation of the human mitochondrial large ribosomal subunit (mtLSU) using endogenous complex purification, in vitro reconstitution and cryo-EM. Structures of transient native mtLSU assembly intermediates that accumulate in GTPBP6-deficient cells reveal how the biogenesis factors GTPBP5, MTERF4 and NSUN4 facilitate PTC folding. Addition of recombinant GTPBP6 reconstitutes late mtLSU biogenesis in vitro and shows that GTPBP6 triggers a molecular switch and progression to a near-mature PTC state. Additionally, cryo-EM analysis of GTPBP6-treated mature mitochondrial ribosomes reveals the structural basis for the dual-role of GTPBP6 in ribosome biogenesis and recycling. Together, these results provide a framework for understanding step-wise PTC folding as a critical conserved quality control checkpoint.

scholarly journals Exploiting GRK2 Inhibition as a Therapeutic Option in Experimental Cancer Treatment: Role of p53-Induced Mitochondrial Apoptosis

Cancers ◽  
2020 ◽  
Vol 12 (12) ◽  
pp. 3530
Author(s):  
Jessica Gambardella ◽  
Antonella Fiordelisi ◽  
Gaetano Santulli ◽  
Michele Ciccarelli ◽  
Federica Andrea Cerasuolo ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Cancer Cell ◽  
Nude Mice ◽  
Specific Inhibitor ◽  
Cancer Cell Proliferation ◽  
In Vivo Models ◽  
P53 Expression

The involvement of GRK2 in cancer cell proliferation and its counter-regulation of p53 have been suggested in breast cancer even if the underlying mechanism has not yet been elucidated. Furthermore, the possibility to pharmacologically inhibit GRK2 to delay cancer cell proliferation has never been explored. We investigated this possibility by setting up a study that combined in vitro and in vivo models to underpin the crosstalk between GRK2 and p53. To reach this aim, we took advantage of the different expression of p53 in cell lines of thyroid cancer (BHT 101 expressing p53 and FRO cells, which are p53-null) in which we overexpressed or silenced GRK2. The pharmacological inhibition of GRK2 was achieved using the specific inhibitor KRX-C7. The in vivo study was performed in Balb/c nude mice, where we treated BHT-101 or FRO-derived tumors with KRX-C7. In our in vitro model, FRO cells were unaffected by GRK2 expression levels, whereas BHT-101 cells were sensitive, thus suggesting a role for p53. The regulation of p53 by GRK2 is due to phosphorylative events in Thr-55, which induce the degradation of p53. In BHT-101 cells, the pharmacologic inhibition of GRK2 by KRX-C7 increased p53 levels and activated apoptosis through the mitochondrial release of cytochrome c. These KRX-C7-mediated events were also confirmed in cancer allograft models in nude mice. In conclusion, our data showed that GRK2 counter-regulates p53 expression in cancer cells through a kinase-dependent activity. Our results further corroborate the anti-proliferative role of GRK2 inhibitors in p53-sensitive tumors and propose GRK2 as a therapeutic target in selected cancers.

scholarly journals Role of PARP1-mediated autophagy in EGFR-TKI resistance in non-small cell lung cancer

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Zhimin Zhang ◽  
Xiaojuan Lian ◽  
Wei Xie ◽  
Jin Quan ◽  
Maojun Liao ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Kinase Inhibitors ◽  
Growth Factor Receptor ◽  
Advanced Lung Cancer ◽  
Tki Resistance ◽  
Geo Dataset ◽  
Epidermal Growth

AbstractResistance to epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) has become the main clinical challenge of advanced lung cancer. This research aimed to explore the role of PARP1-mediated autophagy in the progression of TKI therapy. PARP1-mediated autophagy was evaluated in vitro by CCK-8 assay, clonogenic assay, immunofluorescence, and western blot in the HCC-827, H1975, and H1299 cells treated with icotinib (Ico), rapamycin, and AZD2281 (olaparib) alone or in combination. Our results and GEO dataset analysis confirmed that PARP1 is expressed at lower levels in TKI-sensitive cells than in TKI-resistant cells. Low PARP1 expression and high p62 expression were associated with good outcomes among patients with NSCLC after TKI therapy. AZD2281 and a lysosomal inhibitor reversed resistance to Ico by decreasing PARP1 and LC3 in cells, but an mTOR inhibitor did not decrease Ico resistance. The combination of AZD2281 and Ico exerted a markedly enhanced antitumor effect by reducing PARP1 expression and autophagy in vivo. Knockdown of PARP1 expression reversed the resistance to TKI by the mTOR/Akt/autophagy pathway in HCC-827IR, H1975, and H1299 cells. PARP1-mediated autophagy is a key pathway for TKI resistance in NSCLC cells that participates in the resistance to TKIs. Olaparib may serve as a novel method to overcome the resistance to TKIs.

Sign in / Sign up

Export Citation Format

Share Document