scholarly journals Honokiol induces paraptosis-like cell death of acute promyelocytic leukemia via mTOR & MAPK signaling pathways activation

APOPTOSIS ◽  
2021 ◽  
Author(s):  
Xiaoli Liu ◽  
Yan Gu ◽  
Yaoyao Bian ◽  
Danhong Cai ◽  
Yu Li ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Cell Death ◽  
Endoplasmic Reticulum Stress ◽  
Signaling Pathway ◽  
Acute Promyelocytic Leukemia ◽  
Mapk Signaling ◽  
Promyelocytic Leukemia ◽  
Protein Synthesis Inhibitor ◽  
Protein Accumulation ◽  
Nb4 Cells

AbstractAcute promyelocytic leukemia (APL) is a blood system disease caused by the accumulation of a large number of immature blood cells in bone marrow. Although the introduction of all-trans retinoic acid (ATRA) and arsenic has reached a high level of complete remission rate and 5-year disease-free survival rate, the occurrence of various adverse reactions still severely affects the quality of life of patients. As a natural product, honokiol (HNK) has the advantages of low toxicity and high efficiency, and it is a potential drug for the treatment of cancer. Since cancer cells can escape apoptotic cell death through multiple adaptive mechanisms, HNK, a drug that induces cancer cell death in a nonapoptotic way, has attracted much interest. We found that HNK reduced the viability of human APL cell line (NB4 cells) by inducing paraptosis-like cell death. The process was accompanied by excessive reactive oxygen species (ROS), mitochondrial damage, endoplasmic reticulum stress, and increased microtubule-associated protein 1 light chain 3 (LC3) processing. The inactivation of proteasome activity was the main cause of misfolded and unfolded protein accumulation in endoplasmic reticulum, such as LC3II/I and p62. This phenomenon could be alleviated by adding cycloheximide (CHX), a protein synthesis inhibitor. We found that mTOR signaling pathway participated in paraptosis-like cell death induced by HNK in an autophagy-independent process. Moreover, the mitogen-activated protein kinase (MAPK) signaling pathway induced paraptosis of NB4 cells by promoting endoplasmic reticulum stress. In summary, these findings indicate that paraptosis may be a new way to treat APL, and provide novel insights into the potential mechanism of paraptosis-like cell death.

Aldehyde biphenyl chalcones induce immunogenic apoptotic-like cell death and are promising new safe compounds against a wide range of hematologic cancers

2020 ◽  
Vol 12 (8) ◽  
pp. 673-688
Author(s):  
Mariana F Maioral ◽  
Natália M Stefanes ◽  
Patrícia D Neuenfeldt ◽  
Louise D Chiaradia-Delatorre ◽  
Ricardo J Nunes ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Cell Death ◽  
Endoplasmic Reticulum Stress ◽  
Hematological Malignancies ◽  
Promyelocytic Leukemia ◽  
Leukemic Cells ◽  
Leukemia Cells ◽  
Promyelocytic Leukemia Protein ◽  
Wide Range ◽  
Antileukemic Effect

Aim: Investigate the apoptotic mechanisms of two new aldehyde biphenyl chalcones on leukemia cells. Materials & methods: From a series of 71 new chalcones, we selected the two most cytotoxic. Results: JA3 and JA7 were cytotoxic not only against hematological malignancies but also against solid tumor and cancer stem cells, yet with no toxicity to normal cells. Moreover, they induced immunogenic apoptotic-like cell death independently of promyelocytic leukemia protein, with extensive mitochondrial damages downstream of endoplasmic reticulum stress. Preventing endoplasmic reticulum stress and the upregulation of proapoptotic machinery inhibited JA3- and JA7-induced cell death. Likewise, blocking receptor Fas protected cells from killing. They increased the antileukemic effect of cytarabine and vincristine and killed leukemic cells collected from patients with different acute leukemia subtypes. Conclusion: JA3 and JA7 represent new promising prototypes for the development of new chemotherapeutics.

Fisetin induces apoptosis and endoplasmic reticulum stress in human non-small cell lung cancer through inhibition of the MAPK signaling pathway

Tumor Biology ◽  
2016 ◽  
Vol 37 (7) ◽  
pp. 9615-9624 ◽  
Author(s):  
Kyoung Ah Kang ◽  
Mei Jing Piao ◽  
Susara Ruwan Kumara Madduma Hewage ◽  
Yea Seong Ryu ◽  
Min Chang Oh ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Endoplasmic Reticulum ◽  
Endoplasmic Reticulum Stress ◽  
Small Cell Lung Cancer ◽  
Signaling Pathway ◽  
Cell Lung Cancer ◽  
Mapk Signaling ◽  
Small Cell ◽  
Mapk Signaling Pathway ◽  
Small Cell Lung

scholarly journals Retinoid-induced differentiation of acute promyelocytic leukemia involves PML-RARalpha-mediated increase of type II transglutaminase

Blood ◽  
1996 ◽  
Vol 87 (5) ◽  
pp. 1939-1950 ◽  
Author(s):  
L Benedetti ◽  
F Grignani ◽  
BM Scicchitano ◽  
AM Jetten ◽  
D Diverio ◽  
...  
Keyword(s):  
Cell Line ◽  
Signaling Pathway ◽  
Acute Promyelocytic Leukemia ◽  
Molecular Mechanisms ◽  
Growth Arrest ◽  
Promyelocytic Leukemia ◽  
Leukemic Cells ◽  
Type Ii ◽  
Granulocytic Differentiation ◽  
Nb4 Cells

All-trans retinoic acid (t-RA) administration leads to complete remission in acute promyelocytic leukemia (APL) patients by inducing growth arrest and differentiation of the leukemic clone. In the present study, we show that t-RA treatment dramatically induced type II transglutaminase (type II TGase) expression in cells carrying the t(15;17) translocation and expressing the PML-RARalpha product such as the APL-derived NB4 cell line and fresh leukemic cells from APL patients. This induction correlated with t-RA-induced growth arrest, granulocytic differentiation, and upregulation of the leukocyte adherence receptor beta subunit (CD18) gene expression. The increase in type II TGase was not abolished by cycloheximide treatment, suggesting that synthesis of a protein intermediate was not required for the induction. t-RA did not significantly alter the rate of growth arrest and did not stimulate differentiation and type II TGase activity in NB4.306 cells, a t-RA-resistant subclone of the NB4 cell line, or in leukemic cells derived from two patients morphologically defined as APL but lacking the t(15;17). However, in NB4.306 cells, t-RA treatment was able to increase CD18 mRNA expression in a manner similar to NB4 cells. The molecular mechanisms involved in the induction of these genes were investigated. In NB4 cells, using novel receptor-selective ligands such as 9-cis-RA, TTNPB, AM580, and SR11217, we found that RAR- and RARalpha- selective retinoids were able to induce growth arrest, granulocytic differentiation, and type II TGase, whereas the RXR-selective retinoid SR11217 was inactive. Moreover, an RAR alpha-antagonist completely inhibited the expression of type II TGase and CD18 induced by these selective retinoids in NB4 cells. In NB4.306 cells, an RARalpha- dependent signaling pathway was found involved in the modulation of CD18 expression. In addition, expression of the PML-RARalpha gene in myeloid U937 precursor cells resulted in the ability of these cells to induce type II TGase in response to t-RA. On the basis of these results we hypothesize a specific involvement of a signaling pathway involving PML-RAR alpha for the induction of growth arrest, granulocytic differentiation, and type II TGase by retinoids in APL cells.

scholarly journals Arsenic Trioxide Potentiates Extracellular Traps-Formation Cell Death in Acute Promyelocytic Leukemia through mTOR-Regulated Autophagy

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 1575-1575
Author(s):  
Tao Li ◽  
Muhua Cao ◽  
Ruishuang Ma ◽  
Xiaoming Wu ◽  
Lu Zhao ◽  
...  
Keyword(s):  
Cell Death ◽  
Arsenic Trioxide ◽  
Acute Promyelocytic Leukemia ◽  
Promyelocytic Leukemia ◽  
Extracellular Dna ◽  
Apoptosis Resistance ◽  
Dna Complexes ◽  
Nb4 Cells ◽  
Wide Range

Abstract Background:Emerging clinical data shows that arsenic trioxide (ATO) exerts selective cytotoxicity against acute promyelocytic leukemia (APL) without severe side effects that mainly ascribed to nonspecific induction of apoptosis. It is attractive to speculate whether other uncovered APL cell death exists which can be specifically sparked by ATO administration. We have recently demonstrated that APL cells can undergo a previously unrecognized pathway for death by releasing extracellular DNA traps (ETs), termed ETosis (Ma R et al, Cell Death Dis 2016). However, besides apoptosis, whether ATO induces this APL-specific ETotic cell death remains to be explored. We wereto investigated the effects of a wide range of concentrations of ATO on ETotic death in APL cells and elucidate the underlying molecular mechanisms. Methods: Bone marrow samples were obtained from sixteen APL patients before and after the continuous administration of ATO for two weeks. APL cells were isolated and cultured in the presence and absence of ATRA for 3 days. We used confocal microscopy to image ET formation by APL cells and the percentage of ETotic cells was simultaneously quantified. ELISA was used to measure the concentration of myeloperoxidase (MPO)-DNA complexes in the supernant. We also assessed the effects of a wide range of concentrations (0.1, 0.25, 0.5, 0.75, 1.0, 2.0 μM) of ATO treatment for 24, 48 and 72 hours on ETosis in APL-cell line NB4 cells in vitro. Autophagy activation and leukemia-initiating cell (LIC) activity were evaluated by immunoblotting and imaged by immunostaining. LICs were analyzed using colony-forming unit (CFU) assays, and identified and quantified by flow cytometry. Results: APL cells isolated from ATO-treated APL patients underwent significantly increased spontaneous (P = 0.005) and ATRA-stimulated (P = 0.002) ETosis compared to those from newly diagnosed patients (n = 16). In vitro ATO treatment showed that the percentage of ETotic NB4 cells dramatically increased at 0.5 μM (8 ± 1.6%), peaked at 0.75 μM (15 ± 2.4%) and was gradually suppressed at higher concentrations. The concentration of MPO-DNA complexes, an indirect marker of ETosis, parallelled the dose-dependent change in the percentage of ETotic cells. Interestingly, inhibition experiments indicated that ATO caused concentration-dependent APL cell death: ATO primarily triggered ETosis at moderate concentrations (0.5 to 0.75 μM) and switched to apoptosis at relatively high doses (1.0 to 2.0 μM). Furthermore, We found that ATO induced ETosis through mammalian target of rapamycin (mTOR)-regulated autophagy. Surprisingly, inhibition of ETosis spared LIC activity from ATO reduction, while combined treatment with ATO and rapamycin further increased ETosis-mediated LIC loss (~3.5-fold). Conclusion s : This is the first study to show that ATO potentiates ETotic death in APL cells through mTOR-regulated autophagy. Importantly, further investigation suggests that ATO specifically targets the APL LICs to ETosis. This implies that, in combination with ATO, therapy-triggered ETosis by targeting the corresponding signaling pathways could be a novel and effective strategy to improve a long relapse-free survival through LIC clearance, avoid lethal apoptosis-related complications and overcome apoptosis resistance. Conflict of interest statement: None. Disclosures No relevant conflicts of interest to declare.

Curcumin induces cell death of human papillary thyroid carcinoma BCPAP cells through endoplasmic reticulum stress

RSC Advances ◽  
2016 ◽  
Vol 6 (58) ◽  
pp. 52905-52912 ◽  
Author(s):  
Lixi Zhang ◽  
Li Zhang ◽  
Xian Cheng ◽  
Yanyan Gao ◽  
Jiandong Bao ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Cell Death ◽  
Papillary Thyroid Carcinoma ◽  
Endoplasmic Reticulum Stress ◽  
Thyroid Carcinoma ◽  
Er Stress ◽  
Signaling Pathway ◽  
Papillary Thyroid

Curcumin induced cell death of BCPAP cells via ER stress with activation of the ATF6/XBP-1 signaling pathway and Ca2+ release.

The combination of arsenic and cryptotanshinone induces apoptosis through induction of endoplasmic reticulum stress-reactive oxygen species in breast cancer cells

Metallomics ◽  
2015 ◽  
Vol 7 (1) ◽  
pp. 165-173 ◽  
Author(s):  
Yan Fang Zhang ◽  
Min Zhang ◽  
Xu Lei Huang ◽  
Yu Jie Fu ◽  
Yu Han Jiang ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Reactive Oxygen Species ◽  
Endoplasmic Reticulum ◽  
Endoplasmic Reticulum Stress ◽  
Cancer Cells ◽  
Arsenic Trioxide ◽  
Acute Promyelocytic Leukemia ◽  
Breast Cancer Cells ◽  
Promyelocytic Leukemia ◽  
Oxygen Species

Arsenic trioxide has been successfully used for the treatment of patients with acute promyelocytic leukemia (APL) worldwide.

Sign in / Sign up

Export Citation Format

Share Document