Calebin A, a novel component of turmeric, suppresses NF-κB regulated cell survival and inflammatory gene products leading to inhibition of cell growth and chemosensitization

Cell can integrate the caspase family and mammalian target of rapamycin (mTOR) signaling in response to cellular stress triggered by environment. It is necessary here to elucidate the direct response and interaction mechanism between the two signaling pathways in regulating cell survival and determining cell fate under cellular stress. Members of the caspase family are crucial regulators of inflammation, endoplasmic reticulum stress response and apoptosis. mTOR signaling is known to mediate cell growth, nutrition and metabolism. For instance, over-nutrition can cause the hyperactivation of mTOR signaling, which is associated with diabetes. Nutrition deprivation can inhibit mTOR signaling via SH3 domain-binding protein 4. It is striking that Ras GTPase-activating protein 1 is found to mediate cell survival in a caspase-dependent manner against increasing cellular stress, which describes a new model of apoptosis. The components of mTOR signaling-raptor can be cleaved by caspases to control cell growth. In addition, mTOR is identified to coordinate the defense process of the immune system by suppressing the vitality of caspase-1 or regulating other interferon regulatory factors. The present review discusses the roles of the caspase family or mTOR pathway against cellular stress and generalizes their interplay mechanism in cell fate determination.

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LONP1 and ClpP cooperatively regulate mitochondrial proteostasis for cancer cell survival

Oncogenesis ◽

10.1038/s41389-021-00306-1 ◽

2021 ◽

Vol 10 (2) ◽

Author(s):

Yu Geon Lee ◽

Hui Won Kim ◽

Yeji Nam ◽

Kyeong Jin Shin ◽

Yu Jin Lee ◽

...

Keyword(s):

Cell Death ◽

Cell Growth ◽

Cell Survival ◽

Cancer Cell ◽

Stress Responses ◽

Molecular Mechanisms ◽

Tca Cycle ◽

Mitochondrial Matrix ◽

Mitochondrial Functions ◽

Cancer Cell Survival

AbstractMitochondrial proteases are key components in mitochondrial stress responses that maintain proteostasis and mitochondrial integrity in harsh environmental conditions, which leads to the acquisition of aggressive phenotypes, including chemoresistance and metastasis. However, the molecular mechanisms and exact role of mitochondrial proteases in cancer remain largely unexplored. Here, we identified functional crosstalk between LONP1 and ClpP, which are two mitochondrial matrix proteases that cooperate to attenuate proteotoxic stress and protect mitochondrial functions for cancer cell survival. LONP1 and ClpP genes closely localized on chromosome 19 and were co-expressed at high levels in most human cancers. Depletion of both genes synergistically attenuated cancer cell growth and induced cell death due to impaired mitochondrial functions and increased oxidative stress. Using mitochondrial matrix proteomic analysis with an engineered peroxidase (APEX)-mediated proximity biotinylation method, we identified the specific target substrates of these proteases, which were crucial components of mitochondrial functions, including oxidative phosphorylation, the TCA cycle, and amino acid and lipid metabolism. Furthermore, we found that LONP1 and ClpP shared many substrates, including serine hydroxymethyltransferase 2 (SHMT2). Inhibition of both LONP1 and ClpP additively increased the amount of unfolded SHMT2 protein and enhanced sensitivity to SHMT2 inhibitor, resulting in significantly reduced cell growth and increased cell death under metabolic stress. Additionally, prostate cancer patients with higher LONP1 and ClpP expression exhibited poorer survival. These results suggest that interventions targeting the mitochondrial proteostasis network via LONP1 and ClpP could be potential therapeutic strategies for cancer.

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RETRACTION: A Novel Pentamethoxyflavone Down-Regulates Tumor Cell Survival and Proliferative and Angiogenic Gene Products through Inhibition of IκB Kinase Activation and Sensitizes Tumor Cells to Apoptosis by Cytokines and Chemotherapeutic Agents

Molecular Pharmacology ◽

10.1124/mol.110.067512 ◽

2010 ◽

Vol 79 (2) ◽

pp. 279-289 ◽

Cited By ~ 5

Author(s):

Kanokkarn Phromnoi ◽

Simone Reuter ◽

Bokyung Sung ◽

Sahdeo Prasad ◽

Ramaswamy Kannappan ◽

...

Keyword(s):

Tumor Cell ◽

Cell Survival ◽

Tumor Cells ◽

Chemotherapeutic Agents ◽

Gene Products ◽

Kinase Activation ◽

Iκb Kinase ◽

Tumor Cell Survival ◽

Angiogenic Gene

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Identification of positively and negatively acting elements regulating expression of the E2F2 gene in response to cell growth signals.

Molecular and Cellular Biology ◽

10.1128/mcb.17.9.5227 ◽

1997 ◽

Vol 17 (9) ◽

pp. 5227-5235 ◽

Cited By ~ 138

Author(s):

R Sears ◽

K Ohtani ◽

J R Nevins

Keyword(s):

Cell Growth ◽

Binding Sites ◽

Sequence Comparison ◽

Gene Promoter ◽

Growth Stimulation ◽

Gene Products ◽

Quiescent Cells ◽

Expression Of Genes ◽

E Box ◽

Mammalian Cell Growth

Mammalian cell growth is governed by regulatory activities that include the products of genes such as c-myc and ras that act early in G1, as well as the E2F family of transcription factors that accumulate later in G1 to regulate the expression of genes involved in DNA replication. Previous work has shown that the expression of the E2F1, E2F2, and E2F3 gene products is tightly regulated by cell growth. To further explore the mechanisms controlling accumulation of E2F activity, we have isolated genomic sequences flanking the 5' region of the E2F2 coding sequence. Various assays demonstrate promoter activity in this sequence that reproduces the normal control of E2F2 expression during a growth stimulation. Sequence comparison reveals the presence of a variety of known transcription factor binding sites, including E-box elements that are consensus Myc binding sites, as well as E2F binding sites. We demonstrate that the E-box elements, which we show can function as Myc-responsive sites, contribute in a positive fashion to promoter function. We also find that E2F-dependent negative regulation in quiescent cells plays a significant role in the cell growth-dependent control of the promoter, similar to the regulation of the E2F1 gene promoter.

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Transcription modulation by CDK9 regulates inflammatory genes and RIPK3-MLKL-mediated necroptosis in periodontitis progression

Scientific Reports ◽

10.1038/s41598-019-53910-y ◽

2019 ◽

Vol 9 (1) ◽

Cited By ~ 2

Author(s):

Jiao Li ◽

Jiahong Shi ◽

Yue Pan ◽

Yunhe Zhao ◽

Fuhua Yan ◽

...

Keyword(s):

Gene Expression ◽

Cell Survival ◽

Inflammatory Responses ◽

Inflammatory Diseases ◽

Acute Infection ◽

Infection Process ◽

Inhibitory Protein ◽

Inflammatory Gene ◽

Knock Down

AbstractCyclin-dependent kinase 9 (CDK9), one crucial molecule in promoting the transition from transcription pausing to elongation, is a critical modulator of cell survival and death. However, the pathological function of CDK9 in bacterial inflammatory diseases has never been explored. CDK9 inhibition or knock-down attenuated Porphyromonas gingivalis-triggered inflammatory gene expression. Gene-expression microarray analysis of monocytes revealed that knock-down of CDK9 not only affected inflammatory responses, but also impacted cell death network, especially the receptor-interacting protein kinase 3 (RIPK3)-mixed lineage kinase domain-like (MLKL)-mediated necroptosis after P. gingivalis infection. Inhibition of CDK9 significantly decreased necroptosis with downregulation of both MLKL and phosphorylated MLKL. By regulating caspase-8 and cellular FLICE inhibitory protein (cFLIP), key molecules in regulating cell survival and death, CDK9 affected not only the classic RIPK1-RIPK3-mediated necroptosis, but also the alternate TIR-domain-containing adapter-inducing interferon-β-RIPK3-mediated necroptosis. CDK9 inhibition dampened pro-inflammatory gene production in the acute infection process in the subcutaneous chamber model in vivo. Moreover, CDK9 inhibition contributed to the decreased periodontal bone loss and inflammatory response induced by P. gingivalis in the periodontal micro-environment. In conclusion, by modulating the RIPK3-MLKL-mediated necroptosis, CDK9 inhibition provided a novel mechanism to impact the progress of bacterial infection in the periodontal milieu.

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Targetting an LncRNA P5848-ENO1 axis inhibits tumor growth in hepatocellular carcinoma

Bioscience Reports ◽

10.1042/bsr20180896 ◽

2019 ◽

Vol 39 (11) ◽

Cited By ~ 1

Author(s):

Xidan Zhu ◽

Hui Yu ◽

Baolin Li ◽

Jing Quan ◽

Zhangrui Zeng ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Radiofrequency Ablation ◽

Cell Growth ◽

Tumor Growth ◽

Cell Survival ◽

Cancer Cell ◽

Expression Level ◽

High Recurrence Rate ◽

Gene And Protein Expression ◽

And Migration

Abstract Hepatocellular carcinoma (HCC) has a high recurrence rate and poor clinical outcome after currently used therapies, including radiofrequency ablation. To explore the possible mechanisms for the relapse of HCC, in the present study we focussed on long non-coding RNA (LncRNA), which has been reported to be involved in tumorigenesis. We identified an LncRNA P5848, whose expression level was up-regulated in tumor samples from HCC patients after radiofrequency ablation. As such, we speculated that LncRNA P5848 may play a role in tumor growth. Here we showed that LncRNA P5848, whose up-regulation can lead to HCC cancer cell proliferation and migration. In vitro and in vivo overexpression of LncRNA P5848 promoted cell growth, cell survival, and cell invasion, whereas LncRNA P5848 depletion exerts opposite effects. Mechanistically, we have found that ENO1 was the target of LncRNA P5848. LncRNA P5848 up-regulated the gene and protein expression level of ENO1, promoting tumor growth and cell survival. However, siRNA-mediated knockdown of ENO1 counteracted the effects of LncRNA P5848 on cancer cell growth, cell survival, and migration. Taken together, LncRNA P5848 promotes HCC development by up-regulating ENO1, indicating that LncRNA P5848-ENO1 axis is a potential therapeutic target for the treatment of HCC.

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Synergistic Suppression of Human Multiple Myeloma Cell Growth by the Natural Product TBL-12 in Combination with Low Doses of Velcade: Insight Into Mechanisms

Blood ◽

10.1182/blood.v118.21.5109.5109 ◽

2011 ◽

Vol 118 (21) ◽

pp. 5109-5109

Author(s):

Bhagavathi A Narayanan ◽

Amitabha Mazumder

Keyword(s):

Multiple Myeloma ◽

Survival Rate ◽

Side Effects ◽

Cell Growth ◽

Cell Survival ◽

Treatment Efficacy ◽

Low Doses ◽

Myeloma Cells ◽

Cell Survival Rate ◽

Isobologram Analysis

Abstract Abstract 5109 Targeting Multiple Myeloma (MM) cells with potential natural agents could overcome the side effects of current treatment drugs while increasing the efficacy at very low doses. In this study we tested the efficacy of proteasome inhibitor Velcade (Bortezomib) with TBL-12, (an extract from Sea Cucumber, Unicorn Pacific Corporation) in human myeloma cells. Based on the findings from cell survival and proliferation assays we believe that as a single agent TBL-12 is effective in inducing cell growth inhibition with a dose of 100ug/ml in myeloma cells MM1, U266 and ARP1 cells and 200ug/ml in KMSI cells. We further examined the combined effect of Velcade with TBL-12 to test the hypothesis that a natural agent in combination with a pharmaceutical drug at low doses (but with different modes of action) can reduce toxicity while enhancing the treatment efficacy that may increase the survival rate. In this study we report the in vitro effect of low doses of Velcade in combination with TBL-12. We performed cell survival assays in MM1 and U266 cells using very low doses of Valcade ranging from 1–10ngs/ml in combination with an already established dose for TBL-12 (100ugs/ml) showed a time and dose dependent inhibitory effect on cell growth. We observed a cell survival rate that was reduced from 100 % to 30% at 48h and 20% at 72h (p<0.001) in both MM1 and U266 cells. These findings suggest the possibility of using very low doses of Velcade in combination with TBL-12 to be more effective and reduce the toxicity. Mechanistically, stimulation of MM cells with TNFa could trigger the activation of IL-6 and vasculendothelial growth factor (VEGF) and its receptors which will lead to progressive angiogenesis in preclinical models for myeloma. To address the effect of TBL-12 on angiogenesis, we conducted several independent assays by stimulating MM and U266 cells with TNFa or IL-6 for duration of 8h. First we determined the rate of cell survival in MM1 and U266 cells at different time points of 24, 48 and 72h in cells stimulated with TNFa (5ng/ml) followed by treatment with TBL-12 (100ug/ml) alone and in combination with Velcade. Although our data showed a 50% decrease in the cell survival rate by TBL-12 alone, we observed a significant decrease (70–80%, p<0.001)) in the cell survival rate in combination with Velcade in TNFa stimulated cells compared to the control. Co-culturing of myeloma cells MM1 and U266 with human umbilical vein endothelial cells (HUVEC) followed by treatment with an already established dose of TBL-12 showed a significant decrease (45%) in cells adhering to the surface of HUVEC determined by phase contrast and immunofluorescence microscopic observations. These findings suggest that TBL-12 may have potential to inhibit angiogenesis by targeting VEGF receptors in combination with Velcade at low doses (determined by isobologram analysis). Evidence from Western blot analysis of the MM1 and U266 cells treated with TBL-12 indicates a significant accumulation of caspase -3 and caspase -9 indicating the underlying targets of TBL-12 in mediating apoptosis. Findings on the isobologram analysis indicating synergistic effects exerted by TBL-12 in combination with Velcade on VEGFR1 receptor, and modulation of Bcl2 and Bax that is associated with apoptosis will be discussed during presentation. Overall findings from this study suggest the potential use of TBL-12 in combination with Velcade could improve treatment efficacy with reduced side effects related to high dose toxicity. Currently we are doing trials with TBL-12 at NYUCI and this data could form the basis for future trials. Disclosures: No relevant conflicts of interest to declare.

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Generation of adenosine tri-phosphate in Leishmania donovani amastigote forms

Acta Parasitologica ◽

10.2478/s11686-014-0203-9 ◽

2014 ◽

Vol 59 (1) ◽

Cited By ~ 7

Author(s):

Subhasish Mondal ◽

Jay Roy ◽

Tanmoy Bera

Keyword(s):

Cell Growth ◽

Cell Survival ◽

Complex I ◽

Leishmania Donovani ◽

Complex Iii ◽

Low Oxygen ◽

Atp Production ◽

Substrate Level Phosphorylation ◽

Metabolic Systems ◽

Substrate Level

AbstractLeishmania, the causative agent of various forms of leishmaniasis, is the significant cause of morbidity and mortality. Regarding energy metabolism, which is an essential factor for the survival, parasites adapt to the environment under low oxygen tension in the host using metabolic systems which are very different from that of the host mammals. We carried out the study of susceptibilities to different inhibitors of mitochondrial electron transport chain and studies on substrate level phosphorylation in wild-type L. donovani. The amastigote forms of L. donovani are independent on oxidative phosphorylation for ATP production. Indeed, its cell growth was not inhibited by excess oligomycin and dicyclohexylcarbodiimide, which are the most specific inhibitors of the mitochondrial Fo/F1-ATP synthase. In contrast, mitochondrial complex I inhibitor rotenone and complex III inhibitor antimycin A inhibited amastigote cell growth, suggesting the role of complex I and complex III in cell survival. Complex II appeared to have no role in cell survival. To further investigate the site of ATP production, we studied the substrate level phosphorylation, which was involved in the synthesis of ATP. Succinate-pyruvate couple showed the highest substrate level phosphorylation in amastigotes whereas NADH-fumarate and NADH-pyruvate couples failed to produce ATP. In contrast, NADPH-fumarate showed the highest rate of ATP formation in promastigotes. Therefore, we can conclude that substrate level phosphorylation is essential for the survival of amastigote forms of Leishmania donovani.

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