scholarly journals Crosstalk between NF-κB and Nucleoli in the Regulation of Cellular Homeostasis

Cells ◽  
2018 ◽  
Vol 7 (10) ◽  
pp. 157 ◽  
Author(s):  
Jingyu Chen ◽  
Lesley Stark
Keyword(s):  
Cell Growth ◽  
Small Molecule ◽  
Nuclear Translocation ◽  
Apoptotic Pathway ◽  
Cellular Homeostasis ◽  
Therapeutic Purpose ◽  
Complex Component ◽  
Nucleolar Stress ◽  
Multiple Levels ◽  
Nucleolar Size

Nucleoli are emerging as key sensors of cellular stress and regulators of the downstream consequences on proliferation, metabolism, senescence, and apoptosis. NF-κB signalling is activated in response to a similar plethora of stresses, which leads to modulation of cell growth and death programs. While nucleolar and NF-κB pathways are distinct, it is increasingly apparent that they converge at multiple levels. Exposure of cells to certain insults causes a specific type of nucleolar stress that is characterised by degradation of the PolI complex component, TIF-IA, and increased nucleolar size. Recent studies have shown that this atypical nucleolar stress lies upstream of cytosolic IκB degradation and NF-κB nuclear translocation. Under these stress conditions, the RelA component of NF-κB accumulates within functionally altered nucleoli to trigger a nucleophosmin dependent, apoptotic pathway. In this review, we will discuss these points of crosstalk and their relevance to anti-tumour mechanism of aspirin and small molecule CDK4 inhibitors. We will also briefly the discuss how crosstalk between nucleoli and NF-κB signalling may be more broadly relevant to the regulation of cellular homeostasis and how it may be exploited for therapeutic purpose.

scholarly journals NF-kB Nucleoli Crosstalk in Stress Response and the Regulation of Apoptosis

2018 ◽  
Author(s):  
jingyu Chen ◽  
Lesley A Stark
Keyword(s):  
Stress Response ◽  
Cell Growth ◽  
Small Molecule ◽  
Nuclear Translocation ◽  
Apoptotic Pathway ◽  
Therapeutic Purpose ◽  
Complex Component ◽  
Nucleolar Stress ◽  
Multiple Levels ◽  
Nucleolar Size

Nucleoli are emerging as key sensors of cellular stress and regulators of the downstream consequences on proliferation, metabolism, senescence and apoptosis. NF-kB signalling is activated in response to a similar plethora of stresses, which leads to modulation of cell growth and death programs. Although these pathways are distinct, it is increasingly apparent that they converge at multiple levels. Exposure of cells to certain insults causes a specific type of nucleolar stress that is characterised by degradation of the PolI complex component, TIF-IA, and increased nucleolar size. Recent studies have shown that this atypical nucleolar stress lies upstream of cytosolic IkB degradation and NF-kB nuclear translocation. Under these stress conditions, the RelA component of NF-kB accumulates within functionally altered nucleoli to trigger a nucleophosmin dependent, apoptotic pathway. In this review, we will discuss these points of crosstalk and their relevance to the anti-tumour mechanism of aspirin and small molecule CDK4 inhibitors. We will also briefly discuss how NF-kB-nucleoli crosstalk may be more broadly relevant to the regulation of cellular homeostasis and how it may be exploited for therapeutic purpose.

scholarly journals Small molecule induces mitochondrial fusion for neuroprotection via targeting CK2 without affecting its conventional kinase activity

2021 ◽  
Vol 6 (1) ◽  
Author(s):  
Ke-Wu Zeng ◽  
Jing-Kang Wang ◽  
Li-Chao Wang ◽  
Qiang Guo ◽  
Ting-Ting Liu ◽  
...  
Keyword(s):  
Small Molecule ◽  
Nuclear Translocation ◽  
Fusion Gene ◽  
Artery Occlusion ◽  
Mitochondrial Fusion ◽  
Dependent Manner ◽  
Behavioral Deficits ◽  
Α Subunit ◽  
Cellular Target ◽  
Cerebral Artery Occlusion

AbstractMitochondrial fusion/fission dynamics plays a fundamental role in neuroprotection; however, there is still a severe lack of therapeutic targets for this biological process. Here, we found that the naturally derived small molecule echinacoside (ECH) significantly promotes mitochondrial fusion progression. ECH selectively binds to the previously uncharacterized casein kinase 2 (CK2) α′ subunit (CK2α′) as a direct cellular target, and genetic knockdown of CK2α′ abolishes ECH-mediated mitochondrial fusion. Mechanistically, ECH allosterically regulates CK2α′ conformation to recruit basic transcription factor 3 (BTF3) to form a binary protein complex. Then, the CK2α′/BTF3 complex facilitates β-catenin nuclear translocation to activate TCF/LEF transcription factors and stimulate transcription of the mitochondrial fusion gene Mfn2. Strikingly, in a mouse middle cerebral artery occlusion (MCAO) model, ECH administration was found to significantly improve cerebral injuries and behavioral deficits by enhancing Mfn2 expression in wild-type but not CK2α′+/− mice. Taken together, our findings reveal, for the first time, that CK2 is essential for promoting mitochondrial fusion in a Wnt/β-catenin-dependent manner and suggest that pharmacologically targeting CK2 is a promising therapeutic strategy for ischemic stroke.

scholarly journals Dimeric small molecule agonists of EphA2 receptor inhibit glioblastoma cell growth

2020 ◽  
Vol 28 (18) ◽  
pp. 115656
Author(s):  
Cody M. Orahoske ◽  
Yaxin Li ◽  
Aaron Petty ◽  
Fatma M. Salem ◽  
Jovana Hanna ◽  
...  
Keyword(s):  
Cell Growth ◽  
Small Molecule ◽  
Glioblastoma Cell

scholarly journals Inhibition of GLI-mediated transcription and tumor cell growth by small-molecule antagonists

2007 ◽  
Vol 104 (20) ◽  
pp. 8455-8460 ◽  
Author(s):  
M. Lauth ◽  
A. Bergstrom ◽  
T. Shimokawa ◽  
R. Toftgard
Keyword(s):  
Cell Growth ◽  
Tumor Cell ◽  
Small Molecule ◽  
Tumor Cell Growth

7-hydroxyfrullanolide, isolated from Sphaeranthus indicus, inhibits colorectal cancer cell growth by p53-dependent and -independent mechanism

2018 ◽  
Vol 40 (6) ◽  
pp. 791-804
Author(s):  
Praveen Pandey ◽  
Deepika Singh ◽  
Mohammad Hasanain ◽  
Raghib Ashraf ◽  
Mayank Maheshwari ◽  
...  
Keyword(s):  
Cell Growth ◽  
Anticancer Activity ◽  
Cancer Cell ◽  
Molecular Mechanisms ◽  
Target Genes ◽  
Cancer Cell Growth ◽  
Apoptotic Pathway ◽  
Syngeneic Mouse Model ◽  
Sphaeranthus Indicus

Abstract Sphaeranthus indicus Linn. is commonly used in Indian traditional medicine for management of multiple pathological conditions. However, there are limited studies on anticancer activity of this plant and its underlying molecular mechanisms. Here, we isolated an active constituent, 7-hydroxyfrullanolide (7-HF), from the flowers of this plant, which showed promising chemotherapeutic potential. The compound was more effective in inhibiting in vitro proliferation of colon cancers cells through G2/M phase arrest than other cancer cell lines that were used in this study. Consistent with in vitro data, 7-HF caused substantial regression of tumour volume in a syngeneic mouse model of colon cancer. The molecule triggered extrinsic apoptotic pathway, which was evident as upregulation of DR4 and DR5 expression as well as induction of their downstream effector molecules (FADD, Caspase-8). Concurrent activation of intrinsic pathway was demonstrated with loss of ΔΨm to release pro-apoptotic cytochrome c from mitochondria and activation of downstream caspase cascades (Caspase -9, -3). Loss of p53 resulted in decreased sensitivity of cells towards pro-apoptotic effect of 7-HF with increased number of viable cells indicating p53-dependent arrest of cancer cell growth. This notion was further supported with 7-HF-mediated elevation of endogenous p53 level, decreased expression of MDM2 and transcriptional upregulation of p53 target genes in apoptotic pathway. However, 7-HF was equally effective in preventing progression of HCT116 p53+/+ and p53−/− cell derived xenografts in nude mice, which suggests that differences in p53 status may not influence its in vivo efficacy. Taken together, our results support 7-HF as a potential chemotherapeutic agent and provided a new mechanistic insight into its anticancer activity.

scholarly journals WTIP upregulates FOXO3a and induces apoptosis through PUMA in acute myeloid leukemia

2021 ◽  
Vol 13 (1) ◽  
Author(s):  
Yunqi Zhu ◽  
Xiangmin Tong ◽  
Ying Wang ◽  
Xiaoya Lu
Keyword(s):  
Acute Myeloid Leukemia ◽  
Tumor Suppressor ◽  
Transcriptional Activation ◽  
Myeloid Leukemia ◽  
Molecular Mechanisms ◽  
Nuclear Translocation ◽  
Hematologic Malignancy ◽  
Apoptotic Pathway ◽  
Acute Myeloid

AbstractAcute myeloid leukemia (AML) is an aggressive and heterogeneous clonal hematologic malignancy for which novel therapeutic targets and strategies are required. Emerging evidence suggests that WTIP is a candidate tumor suppressor. However, the molecular mechanisms of WTIP in leukemogenesis have not been explored. Here, we report that WTIP expression is significantly reduced both in AML cell lines and clinical specimens compared with normal controls, and low levels of WTIP correlate with decreased overall survival in AML patients. Overexpression of WTIP inhibits cell proliferation and induces apoptosis both in vitro and in vivo. Mechanistic studies reveal that the apoptotic function of WTIP is mediated by upregulation and nuclear translocation of FOXO3a, a member of Forkhead box O (FOXO) transcription factors involved in tumor suppression. We further demonstrate that WTIP interacts with FOXO3a and transcriptionally activates FOXO3a. Upon transcriptional activation of FOXO3a, its downstream target PUMA is increased, leading to activation of the intrinsic apoptotic pathway. Collectively, our results suggest that WTIP is a tumor suppressor and a potential target for therapeutic intervention in AML.

scholarly journals Ganoderma tsugae Inhibits the SREBP-1/AR Axis Leading to Suppression of Cell Growth and Activation of Apoptosis in Prostate Cancer Cells

Molecules ◽  
2018 ◽  
Vol 23 (10) ◽  
pp. 2539 ◽  
Author(s):  
Shih-Yin Huang ◽  
Guan-Jhong Huang ◽  
Hsi-Chin Wu ◽  
Ming-Ching Kao ◽  
Wen-Chin Huang
Keyword(s):  
Prostate Cancer ◽  
Cell Growth ◽  
Regulatory Element ◽  
Specific Antigen ◽  
Herbal Product ◽  
Ethanol Extract ◽  
Apoptotic Pathway ◽  
Castration Resistant ◽  
Element Binding Protein ◽  
Sterol Regulatory Element

Recent research suggests that the activation of lipid biosynthesis (lipogenesis) is linked with prostate cancer (PCa) malignancy. Sterol regulatory element-binding protein-1 (SREBP-1) is a key transcriptional regulator controlling lipogenesis. Moreover, androgen receptor (AR) has been well defined to play an important role in lethal PCa aggressiveness from androgen-responsive to castration-resistant status. In this study, we showed that the quality-assured Ganoderma tsugae ethanol extract (GTEE), a Chinese natural and herbal product, significantly inhibited expression of SREBP-1 and its downstream genes associated with lipogenesis in PCa cells. Through inhibiting SREBP-1, GTEE reduced the levels of intracellular fatty acids and lipids in PCa cells. Importantly, GTEE also downregulated the expression of AR and prostate-specific antigen (PSA) in both androgen-responsive and castration-resistant PCa cells. By blocking the SREBP-1/AR axis, GTEE suppressed cell growth and progressive behaviors, as well as activating the caspase-dependent apoptotic pathway in PCa cells. These data provide a new molecular basis of GTEE for the development of a potential therapeutic approach to treat PCa malignancy.

Abstract 1790: Small molecule inhibitors of QSOX1 suppress tumor cell growth and invasion

2014 ◽  
Author(s):  
Paul D. Hanavan ◽  
Douglas O. Faigel ◽  
Chen-Ting Ma ◽  
Eduard Sergienko ◽  
Nathalie Meurice ◽  
...  
Keyword(s):  
Cell Growth ◽  
Tumor Cell ◽  
Small Molecule ◽  
Small Molecule Inhibitors ◽  
Tumor Cell Growth

Abstract 2544: Combination of anti-cancer small molecule tolfenamic acid and curcumin effectively inhibits colon cancer cell growth

2015 ◽  
Author(s):  
Umesh T. Sankpal ◽  
Ganji Purnachandra Nagaraju ◽  
Myrna Hurtado ◽  
Sriharika R. Gottipolu ◽  
Bassel El-Rayes ◽  
...  
Keyword(s):  
Colon Cancer ◽  
Cell Growth ◽  
Cancer Cell ◽  
Small Molecule ◽  
Tolfenamic Acid ◽  
Colon Cancer Cell ◽  
Cancer Cell Growth ◽  
Anti Cancer
Sign in / Sign up

Export Citation Format

Share Document