scholarly journals Inhibition of JK184-Induced Cytoprotective Autophagy Potentiates JK184 Antitumor Effects in Breast Cancer

2020 ◽  
Vol 2020 ◽  
pp. 1-12
Author(s):  
Xiaoya Xi ◽  
Tao He
Keyword(s):  
Breast Cancer ◽  
Cell Death ◽  
Transcriptional Activity ◽  
Therapeutic Strategy ◽  
Therapeutic Options ◽  
Time Dependent ◽  
Dependent Manner ◽  
Antitumor Effects ◽  
Aggressive Tumor ◽  
Hedgehog Inhibitor

Breast cancer (BCa) is the most common aggressive tumor with limited curative therapeutic options available among women worldwide. JK184 is a potent Hedgehog inhibitor that regulates the glioma-dependent transcriptional activity. Although some studies have indicated that JK184 can kill BCa cells, it remains unclear whether there are any events that limit the use of JK184 in BCa therapy. Here, we report that JK184 intervention induces BCa cell death involving the dysregulation of autophagy in a dose- and time-dependent manner. The induction of autophagy compromises the antiproliferative effect of JK184. Mechanistically, JK184 induces autophagy via inhibiting the Akt/mTOR pathway in BCa cells. Taken together, our findings unravel a novel mechanism for JK184 treatment in BCa, suggesting that JK184 in combination with autophagy inhibitor may be a potential therapeutic strategy for the clinical treatment of BCa.

scholarly journals TB-4 Antitumor effects of a novel curcumin derivative curcumin monoglucuronide on glioblastoma cells in vitro and in vivo

2021 ◽  
Vol 3 (Supplement_6) ◽  
pp. vi6-vi6
Author(s):  
Takashi Fujii ◽  
Shun Yamamuro ◽  
Masamichi Takahashi ◽  
Akihide Kondo ◽  
Yoshitaka Narita ◽  
...  
Keyword(s):  
Cell Death ◽  
Water Soluble ◽  
Dependent Manner ◽  
Antitumor Effects ◽  
Multiple Cell ◽  
Human Gbm ◽  
Dose Dependent ◽  
Novel Therapeutic

Abstract The therapeutic outcome of glioblastomas (GBMs) is still very poor. Therefore, invention of novel therapeutic methods against GBM cases is considered urgent. The antitumor effects of naturally-derived compounds are attracting attention recently, and therapeutic efficacy of curcumin, a plant-derived compound previously used for multiple purpose, has been indicated in many cancer systems; however, clinical application of curcumin is considered difficult because of its poor bioavailability (under 1 %). Curcumin monoglucuronide (CMG), a water-soluble prodrug of curcumin recently developed for overcoming this weakness, has been demonstrated excellent antitumor effects for several malignancies in vitro and in vivo; therefore, we investigated the effects of CMG against GBM cells. CMG induced cell death of human GBM cells lines (T98G, U251MG, and U87MG) by dose dependent manner by triggering multiple forms of cell death such as apoptosis and perthanatos. Immunoblotting of CMG-treated GBM cell lysates demonstrated activation of multiple cell death signaling. Furthermore, immunodeficiency mice harboring intracerebral U87MG cell xenografts systemically treated by CMG showed significantly prolonged survival compared with control mice. These results suggest CMG would be a novel therapeutic agent against GBM cases.

scholarly journals Antitumor effects of the small molecule DMAMCL in neuroblastoma via suppressing aerobic glycolysis and targeting PFKL

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Simeng Zhang ◽  
Zhongyan Hua ◽  
Gen Ba ◽  
Ning Xu ◽  
Jianing Miao ◽  
...  
Keyword(s):  
Cell Death ◽  
Synergistic Effects ◽  
Aerobic Glycolysis ◽  
Single Agent ◽  
Molecular Compound ◽  
Dependent Manner ◽  
Antitumor Effects ◽  
Atp Production

Abstract Background Neuroblastoma (NB) is a common solid malignancy in children that is associated with a poor prognosis. Although the novel small molecular compound Dimethylaminomicheliolide (DMAMCL) has been shown to induce cell death in some tumors, little is known about its role in NB. Methods We examined the effect of DMAMCL on four NB cell lines (NPG, AS, KCNR, BE2). Cellular confluence, survival, apoptosis, and glycolysis were detected using Incucyte ZOOM, CCK-8 assays, Annexin V-PE/7-AAD flow cytometry, and Seahorse XFe96, respectively. Synergistic effects between agents were evaluated using CompuSyn and the effect of DMAMCL in vivo was evaluated using a xenograft mouse model. Phosphofructokinase-1, liver type (PFKL) expression was up- and down-regulated using overexpression plasmids or siRNA. Results When administered as a single agent, DMAMCL decreased cell proliferation in a time- and dose-dependent manner, increased the percentage of cells in SubG1 phase, and induced apoptosis in vitro, as well as inhibiting tumor growth and prolonging survival in tumor-bearing mice (NGP, BE2) in vivo. In addition, DMAMCL exerted synergistic effects when combined with etoposide or cisplatin in vitro and displayed increased antitumor effects when combined with etoposide in vivo compared to either agent alone. Mechanistically, DMAMCL suppressed aerobic glycolysis by decreasing glucose consumption, lactate excretion, and ATP production, as well as reducing the expression of PFKL, a key glycolysis enzyme, in vitro and in vivo. Furthermore, PFKL overexpression attenuated DMAMCL-induced cell death, whereas PFKL silencing promoted NB cell death. Conclusions The results of this study suggest that DMAMCL exerts antitumor effects on NB both in vitro and in vivo by suppressing aerobic glycolysis and that PFKL could be a potential target of DMAMCL in NB.

scholarly journals St. John’s Wort Suppresses Growth in Triple-Negative Breast Cancer Cell Line MDA-MB-231 by Inducing Prodeath Autophagy and Apoptosis

Nutrients ◽  
2020 ◽  
Vol 12 (10) ◽  
pp. 3175
Author(s):  
Mikyoung You ◽  
Young-Hyun Lee ◽  
Hwa-Jin Kim ◽  
Ji Hyun Kook ◽  
Hyeon-A Kim
Keyword(s):  
Breast Cancer ◽  
Cell Death ◽  
Cell Line ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Apoptotic Cell ◽  
Cancer Cell Line ◽  
Dependent Manner ◽  
St John’S Wort ◽  
St John's Wort

The rational regulation of programmed cell death by means of autophagy and apoptosis has been considered a potential treatment strategy for cancer. We demonstrated the inhibitory effect of St. John’s Wort (SJW) on growth in the triple-negative breast cancer (TNBC) cell line and xenografted mice and its target mechanism concerning autophagic and apoptotic cell death. SJW ethanol extract (SJWE) inhibited proliferation in a dose-dependent manner. SJWE treatment dramatically increased autophagy flux and apoptosis compared with the control. The autophagy inhibitor, 3-methyladenine (3-MA), reversed the SJWE-induced inhibition of cell proliferation and regulation of autophagy and apoptosis, indicating that SJWE induced apoptosis through prodeath autophagy. Furthermore, SJWE inhibited tumor growth and induced autophagy and apoptosis in the tumor of MDA-MB-231 xenografted athymic nude mice. Our results indicate that SJWE might have great potential as a new anticancer therapy for triple-negative breast cancer by inducing prodeath autophagy and apoptosis.

scholarly journals TiPARP forms nuclear condensates to degrade HIF-1α and suppress tumorigenesis

2020 ◽  
Vol 117 (24) ◽  
pp. 13447-13456 ◽  
Author(s):  
Lu Zhang ◽  
Ji Cao ◽  
Longying Dong ◽  
Hening Lin
Keyword(s):  
Transcription Factors ◽  
Transcriptional Activity ◽  
Nuclear Bodies ◽  
Dependent Manner ◽  
Antitumor Effects ◽  
Adp Ribosylation ◽  
Activation Of Transcription ◽  
Xenograft Models ◽  
Adp Ribosyltransferase ◽  
Feedback Regulator

Precisely controlling the activation of transcription factors is crucial for physiology. After a transcription factor is activated and carries out its transcriptional activity, it also needs to be properly deactivated. Here, we report a deactivation mechanism of HIF-1 and several other oncogenic transcription factors. HIF-1 promotes the transcription of an ADP ribosyltransferase, TiPARP, which serves to deactivate HIF-1. Mechanistically, TiPARP forms distinct nuclear condensates or nuclear bodies in an ADP ribosylation-dependent manner. The TiPARP nuclear bodies recruit both HIF-1α and an E3 ubiquitin ligase HUWE1, which promotes the ubiquitination and degradation of HIF-1α. Similarly, TiPARP promotes the degradation of c-Myc and estrogen receptor. By suppressing HIF-1α and other oncogenic transcription factors, TiPARP exerts strong antitumor effects both in cell culture and in mouse xenograft models. Our work reveals TiPARP as a negative-feedback regulator for multiple oncogenic transcription factors, provides insights into the functions of protein ADP-ribosylation, and suggests activating TiPARP as an anticancer strategy.

Baicalein Cardioprotection via Oxidant Scavenging and Akt-Nitric Oxide Signaling: Identification of Early Reperfusion Phase as the Critical Therapeutic Window

2019 ◽  
Vol 47 (05) ◽  
pp. 1043-1056 ◽  
Author(s):  
Wei-Tien Chang ◽  
Chang-Qing Li ◽  
Chin-Wan Hsu ◽  
Chunpei Lee ◽  
Hsien-Hao Huang ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Cell Death ◽  
Ischemia Reperfusion ◽  
Time Dependent ◽  
Therapeutic Window ◽  
No Production ◽  
Dependent Manner ◽  
Ros Scavenging ◽  
Early Reperfusion ◽  
Reperfusion Phase

Baicalein is a natural flavonoid with anti-oxidant activities protecting against ischemia/reperfusion (I/R) injury. Previous studies suggest that oxidative burst early after reperfusion accelerates cell death. We therefore investigated the critical therapeutic window of baicalein by examining the timing of baicalein treatment in relation to its oxidant modulating and cytoprotective effects. Using an established chick cardiomyocyte model of I/R, we administered baicalein at various time points after reperfusion and assessed cell viability and the profiles of reactive oxygen species (ROS), nitric oxide (NO), and Akt phosphorylation. Baicalein administered at the onset of reperfusion resulted in a concentration-dependent reduction of cell death (25 [Formula: see text]M [Formula: see text]%, 50[Formula: see text][Formula: see text]M [Formula: see text]%, 100[Formula: see text][Formula: see text]M [Formula: see text]%, vs. I/R control [Formula: see text]%, all [Formula: see text]). Baicalein (100[Formula: see text][Formula: see text]M) timely and effectively scavenged ROS burst and enhanced NO production in the early reperfusion phase. Cotreatment with NO synthase (NOS) inhibitor l-NAME (200[Formula: see text][Formula: see text]M) partially abrogated the cytoprotective effect. Baicalein (100[Formula: see text][Formula: see text]M) given after reperfusion lost protective effect in a time-dependent manner with cytoprotection completely lost if [Formula: see text][Formula: see text]min. Even with only 15-min delay after reperfusion, the ROS scavenging effect was abolished and the NO enhancing effect markedly reduced. The phosphorylation of Akt, an upstream regulator of eNOS, also diminished as the delay lengthened. In conclusion, baicalein treatment after reperfusion confers cardioprotection in a concentration- and time-dependent manner. The critical therapeutic window lies in the early reperfusion phase, during which ROS scavenging and Akt-eNOS mediated NO signaling are most effective.

JAZ Is Required for Interlukin-3 Withdrawal-Induced Apoptosis by Directly Activating p53.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 1445-1445
Author(s):  
Mingli Yang ◽  
Jingxin Qiu ◽  
Ying Li ◽  
Jinghua Jia ◽  
W. Stratford May
Keyword(s):  
Cell Death ◽  
Zinc Finger ◽  
Cell Response ◽  
Transcriptional Activity ◽  
Lymphoid Cells ◽  
Hematopoietic Cell ◽  
Hematopoietic Progenitor Cell ◽  
Dependent Manner ◽  
Hematopoietic Progenitor ◽  
P53 Expression

Abstract By screening a murine interleukin-3 (IL-3)-dependent myeloid cell cDNA library, we previously identified JAZ (Just Another Zinc Finger Protein), a novel zinc finger (ZF) protein that localizes in the nucleus and preferentially binds dsRNA rather than DNA. Forced overexpression of JAZ induces apoptosis but the mechanism was not known. JAZ is differentially expressed in CD34+ primary human and mouse bone marrow cells including mononuclear myeloid and lymphoid cells but not in multinuclear megakaryocytes, indicating that JAZ may function in hematopoietic progenitor cells. Since IL-3 withdrawal induces apoptosis in factor-dependent myeloid and lymphoid cells, we tested whether endogenous JAZ is involved. Hematopoietic cell lines including murine NFS/N1.H7, 32D myeloid and BaF3 lymphoid cells were deprived of IL-3 for 0, 0.5, 1, 2, 4, 6, 8, 12, 24 and/or 48 hr. Results reveal that JAZ expression is upregulated prior to induction of cell death. While a role for p53 in hematopoietic progenitor cell response to apoptosis-inducing stress has been postulated, the mechanism is not clear. Therefore, we assessed whether p53 expression or activation can be affected by JAZ. Results reveal that in association with JAZ upregulation, IL-3 withdrawal also induces p53 expression and importantly, up-regulates its transcriptional activity as assessed by increased BAX expression. To verify p53 dependency, p53-deficient murine M1 and human K562 leukemic cells were also tested. These p53-deficient cells are highly insensitive to serum withdrawal-induced cell death. Importantly, siRNA-mediated ‘knock-down’ of endogenous JAZ (by 70–80%) attenuates stress-induced cell death in NFS/N1.H7 but not M1 cells. These data point to a necessary role for JAZ in IL-3 or growth factor withdrawal-induced hematopoietic cell death in a p53-dependent manner. Further analysis using co-immunoprecipitation studies indicates that endogenous JAZ and p53 associate upon IL-3 withdrawal. Furthermore, using p53+/+ and p53−/− isogenic murine embryonic fibroblasts (MEFs), we clearly show that JAZ not only directly interacts with p53 but also stimulates its transcriptional activity, resulting in mediation/acceleration of stress-activated, p53-dependent apoptosis. Therefore, we propose that the nuclear factor JAZ may be a novel regulator of p53 in the hematopoietic cell response to stress leading to apoptosis. Since only about 15% of hematologic-malignancies express mutant (transcriptionally inactive) p53, it may be possible to therapeutically target wild-type p53 through a mechanism involving JAZ.

γ-Tocotrienol-induced endoplasmic reticulum stress and autophagy act concurrently to promote breast cancer cell death

2015 ◽  
Vol 93 (4) ◽  
pp. 306-320 ◽  
Author(s):  
Roshan V. Tiwari ◽  
Parash Parajuli ◽  
Paul W. Sylvester
Keyword(s):  
Breast Cancer ◽  
Endoplasmic Reticulum ◽  
Cell Death ◽  
Er Stress ◽  
Cancer Cell ◽  
Human Breast Cancer ◽  
Beclin 1 ◽  
Time Dependent ◽  
Human Breast ◽  
Cancer Cell Death

The anticancer effects of γ-tocotrienol are associated with the induction of autophagy and endoplasmic reticulum (ER) stress-mediated apoptosis, but a direct relationship between these events has not been established. Treatment with 40 μmol/L of γ-tocotrienol caused a time-dependent decrease in cancer cell viability that corresponds to a concurrent increase in autophagic and endoplasmic reticulum (ER) stress markers in MCF-7 and MDA-MB-231 human breast cancer cells. γ-Tocotrienol treatment was found to cause a time-dependent increase in early phase (Beclin-1, LC3B-II) and late phase (LAMP-1 and cathepsin-D) autophagy markers, and pretreatment with autophagy inhibitors Beclin-1 siRNA, 3-MA or Baf1 blocked these effects. Furthermore, blockage of γ-tocotrienol-induced autophagy with Beclin-1 siRNA, 3-MA, or Baf1 induced a modest, but significant, reduction in γ-tocotrienol-induced cytotoxicity. γ-Tocotrienol treatment was also found to cause a decrease in mitogenic Erk1/2 signaling, an increase in stress-dependent p38 and JNK1/2 signaling, as well as an increase in ER stress apoptotic markers, including phospho-PERK, phospho-eIF2α, Bip, IRE1α, ATF-4, CHOP, and TRB3. In summary, these finding demonstrate that γ-tocotrienol-induced ER stress and autophagy occur concurrently, and together act to promote human breast cancer cell death.

scholarly journals Isocudraxanthone K Induces Growth Inhibition and Apoptosis in Oral Cancer Cells via Hypoxia Inducible Factor-1α

2014 ◽  
Vol 2014 ◽  
pp. 1-14 ◽  
Author(s):  
Mee-Ran Shin ◽  
Hwa-Jeong Lee ◽  
Soo-Kyung Kang ◽  
Q-Schick Auh ◽  
Young-Man Lee ◽  
...  
Keyword(s):  
Oral Cancer ◽  
Nuclear Translocation ◽  
Hypoxia Inducible Factor ◽  
Signal Transduction Pathway ◽  
Annexin V ◽  
Time Dependent ◽  
Drug Candidate ◽  
Root Bark ◽  
Dependent Manner ◽  
Antitumor Effects

Isocudraxanthone K (IK) is a novel, natural compound from a methanol extract of the root bark ofCudrania tricuspidata. It has not been shown previously that IK possessed antitumor activity. We investigated the antitumor effects and molecular mechanism of IK and related signal transduction pathway(s) in oral squamous cell carcinoma cells (OSCCCs). The MTT assay revealed that IK had an antiproliferative effect on OSCCCs, in a dose- and time-dependent manner. IK induced apoptosis in OSCCCs, as identified by a cell-cycle analysis, annexin V-FITC and propidium iodide staining, and the nuclear morphology in cell death. IK caused time-dependent phosphorylation of Akt, p38, and ERK (extracellular signal-regulated kinase). In addition, IK increased the cytosolic to nuclear translocation of nuclear factor-κB (NF-κB) p65 and the degradation and phosphorylation of IκB-αin HN4 and HN12 cells. Furthermore, IK treatment downregulated hypoxia-inducible factor 1α(HIF-1α) and its target gene, vascular endothelial growth factor (VEGF). Cobalt chloride (CoCl2), a HIF-1αactivator, attenuated the IK-induced growth-inhibiting and apoptosis-inducing effects, and blocked IK-induced expression of apoptosis regulatory proteins, such as Bax, Bcl-2, caspase-3, caspase-8, and caspase-9, and cytochrome c. Collectively, these data provide the first evidence of antiproliferative and apoptosis-inducing effects of IK as a HIF-1αinhibitor and suggest it may be a drug candidate for chemotherapy against oral cancer.

scholarly journals The Corepressor mSin3A Regulates Phosphorylation-Induced Activation, Intranuclear Location, and Stability of AML1

2004 ◽  
Vol 24 (3) ◽  
pp. 1033-1043 ◽  
Author(s):  
Yoichi Imai ◽  
Mineo Kurokawa ◽  
Yuko Yamaguchi ◽  
Koji Izutsu ◽  
Eriko Nitta ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Protein Modification ◽  
Transcriptional Activity ◽  
Regulatory Mechanism ◽  
Dna Binding Protein ◽  
Time Dependent ◽  
Myeloid Differentiation ◽  
Dependent Manner ◽  
Extracellular Signal Regulated Kinase ◽  
Extracellular Signal

ABSTRACT The AML1 (RUNX1) gene, one of the most frequent targets of translocations associated with human leukemias, encodes a DNA-binding protein that plays pivotal roles in myeloid differentiation through transcriptional regulation of various genes. Previously, we reported that AML1 is phosphorylated on two serine residues with dependence on activation of extracellular signal-regulated kinase, which positively regulates the transcriptional activity of AML1. Here, we demonstrate that the interaction between AML1 and the corepressor mSin3A is regulated by phosphorylation of AML1 and that release of AML1 from mSin3A induced by phosphorylation activates its transcriptional activity. Furthermore, phosphorylation of AML1 regulates its intranuclear location and disrupts colocalization of AML1 with mSin3A in the nuclear matrix. PEBP2β/CBFβ, a heterodimeric partner of AML1, was shown to play a role in protecting AML1 from proteasome-mediated degradation. We show that mSin3A also protects AML1 from proteasome-mediated degradation and that phosphorylation-induced release of AML1 from mSin3A results in degradation of AML1 in a time-dependent manner. This study provides a novel regulatory mechanism for the function of transcription factors mediated by protein modification and interaction with cofactors.

scholarly journals Dihydroartemisinin-Transferrin Adducts Enhance TRAIL-Induced Apoptosis in Triple-Negative Breast Cancer in a P53-Independent and ROS-Dependent Manner

2022 ◽  
Vol 11 ◽  
Author(s):  
Xinyu Zhou ◽  
Abel Soto-Gamez ◽  
Fleur Nijdam ◽  
Rita Setroikromo ◽  
Wim J. Quax
Keyword(s):  
Breast Cancer ◽  
Cell Death ◽  
Cell Lines ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Breast Cancer Subtype ◽  
Death Receptor ◽  
Dependent Manner ◽  
Tnbc Cell ◽  
Induced Apoptosis

Triple-negative breast cancer (TNBC) is a highly aggressive breast cancer subtype independent of estrogen receptor, progesterone receptor, or human epidermal growth factor receptor 2. It has a poor prognosis and high recurrence. Due to its limited treatment options in the clinic, novel therapies are urgently needed. Single treatment with the death receptor ligand TRAIL was shown to be poorly effective. Recently, we have shown that artemisinin derivatives enhance TRAIL-induced apoptosis in colon cancer cells. Here, we utilized transferrin (TF) to enhance the effectiveness of dihydroartemisinin (DHA) in inducing cell death in TNBC cell lines (MDA-MB-231, MDA-MB-436, MDA-MB-468 and BT549). We found that the combination of DHA-TF and the death receptor 5-specific TRAIL variant DHER leads to an increase in DR5 expression in all four TNBC cell lines, while higher cytotoxicity was observed in MDA-MB-231, and MDA-MB-436. All the data point to the finding that DHA-TF stimulates cell death in TNBC cells, while the combination of DHA-TF with TRAIL variants will trigger more cell death in TRAIL-sensitive cells. Overall, DHA-TF in combination with TRAIL variants represents a potential novel combination therapy for triple-negative breast cancer.

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