Chk1 Inhibitor Induced DNA Damage Increases BFL1 and Decreases BIM but Does Not Protect Human Cancer Cell Lines From Chk1 Inhibitor-induced Apoptosis

2021 ◽  
Author(s):  
Andrew J. Massey
Keyword(s):  
Dna Damage ◽  
Cell Lines ◽  
Human Cancer ◽  
Rare Event ◽  
Human Cancer Cell Lines ◽  
Basal Expression ◽  
Dna Damaging Agents ◽  
Chk1 Inhibitor ◽  
U2os Cells ◽  
Induced Apoptosis

Abstract V158411 is a potent, selective Chk1 inhibitor currently in pre-clinical development. We utilised RNAseq to evaluate the gene responses to V158411 treatment. BCL2A1 was highly upregulated in U2OS cells in response to V158411 treatment with BCL2A1 mRNA increased >400-fold in U2OS but not HT29 cells. Inhibitors of Chk1, Wee1 and topoisomerases but not other DNA damaging agents or inhibitors of ATR, ATM or DNA-PKcs increased BFL1 and decreased BIM protein. Increased BFL1 appeared limited to a subset of approximately 35% of U2OS cells. Out of 24 cell lines studied, U2OS cells were unique in being the only cell line with low basal BFL1 levels to be increased in response to DNA damage. Induction of BFL1 in U2OS cells appeared dependent on PI3K/AKT/mTOR/MEK pathway signalling but independent of NF-κB transcription factors. Inhibitors of MEK, mTOR and PI3K effectively blocked the increase in BFL1 following V15841 treatment. Increased BFL1 expression did not block apoptosis in U2OS cells in response to V158411 treatment and cells with high basal expression of BFL1 readily underwent caspase-dependent apoptosis following Chk1 inhibitor therapy. BFL1 induction in response to Chk1 inhibition appeared to be a rare event that was dependent on MEK/PI3K/AKT/mTOR signalling.

High-risk HPV-positive human cancer cell lines show different sensitivity to cisplatin-induced apoptosis correlated with the p21Waf1/Cip1 level

1996 ◽  
Vol 108 (1) ◽  
pp. 15-23 ◽  
Author(s):  
Kohsei Funaoka ◽  
Masanobu Shindoh ◽  
Toshiharu Yamashita ◽  
Kei Fujinaga ◽  
Akira Amemiya ◽  
...  
Keyword(s):  
High Risk ◽  
Cell Lines ◽  
Cancer Cell ◽  
Human Cancer ◽  
Cancer Cell Lines ◽  
Human Cancer Cell ◽  
Human Cancer Cell Lines ◽  
Induced Apoptosis ◽  
High Risk Hpv

scholarly journals Nitrosylcobalamin Promotes Cell Death via S Nitrosylation of Apo2L/TRAIL Receptor DR4

2006 ◽  
Vol 26 (15) ◽  
pp. 5588-5594 ◽  
Author(s):  
Zhuo Tang ◽  
Joseph A. Bauer ◽  
Bei Morrison ◽  
Daniel J. Lindner
Keyword(s):  
Cell Death ◽  
Cell Lines ◽  
Human Cancer ◽  
Death Receptor ◽  
The Other ◽  
Caspase 8 ◽  
Trail Receptor ◽  
Wild Type ◽  
Human Cancer Cell Lines ◽  
Induced Apoptosis

ABSTRACT We have previously demonstrated that nitrosylcobalamin (NO-Cbl), an analogue of vitamin B12 that delivers nitric oxide (NO), had potent antiproliferative activity against several human cancer cell lines. NO-Cbl induced apoptosis via a death receptor/caspase-8 pathway. In this study, we demonstrate that a functional Apo2L/TRAIL receptor was necessary for the induction of cell death by NO-Cbl. Furthermore, the Apo2L/TRAIL death receptor DR4 (TRAIL R1) was S nitrosylated following NO-Cbl treatment. Human melanoma (A375), renal carcinoma (ACHN), and ovarian carcinoma (NIH-OVCAR-3) cells were treated with NO-Cbl and subjected to the biotin switch assay; S-nitrosylated DR4 was detected in all three cell lines. NO-Cbl treatment did not cause S nitrosylation of DR5. The seven cysteine residues located in the cytoplasmic domain of DR4 were individually point mutated to alanines. NIH-OVCAR-3 cells expressing the DR4 C336A mutation lacked S nitrosylation following NO-Cbl treatment. Overexpression of wild-type DR4 sensitized cells to growth inhibition by NO-Cbl. Cells expressing the DR4 C336A mutant were more resistant to NO-Cbl and Apo2L/TRAIL than were the other six C-A mutations or wild-type cells. The C336A mutant also displayed blunted caspase-8 enzymatic activity following NO-Cbl treatment compared to the other mutants. Thus, DR4 residue C336 becomes S nitrosylated and promotes apoptosis following NO-Cbl treatment.

scholarly journals Cytotoxic and Pro-apoptotic Activities of Sesquiterpene Lactones from Inula Britannica

2016 ◽  
Vol 11 (1) ◽  
pp. 1934578X1601100
Author(s):  
Ping Xiang ◽  
Xin Guo ◽  
Yang-Yang Han ◽  
Jin-Ming Gao ◽  
Jiang-Jiang Tang
Keyword(s):  
Cell Lines ◽  
Cancer Cell ◽  
Human Cancer ◽  
Sesquiterpene Lactones ◽  
Cancer Cell Lines ◽  
Reference Drug ◽  
Biological Assays ◽  
Human Cancer Cell Lines ◽  
Inula Britannica ◽  
Induced Apoptosis

In this study, five known sesquiterpene lactones (STL) with an α-methylene-γ-lactone motif, including two eudesmanolides, 1β-hydroxyalantolactone (1) and ivangustin (2), and three 1,10-seco-eudesmanolides, 1- O-acetylbritannilactone (3), 1,6- O, O-diacetylbritannilactone (4), and 6α- O(2-methylbutyryl)britannilactone (5) were isolated from the flower heads of the medicinal plant Inula britannica. Their structures were characterized by spectroscopic methods. X-ray data of 2 is reported for the first time. Among them, eudesmanolides 1 and 2 exhibited remarkable cytotoxicity against HEp2, SGC-7901 and HCT116 human cancer cell lines, comparable with etoposide (Vp-16) used as reference drug. Furthermore, treatment of HEp2 cells with 1 induced apoptosis associated with cleaved procaspase-3 and PARP. The biological assays carried out with normal cells (CHO) revealed that all sesquiterpenes were weakly selective against the cancer cell lines tested.

scholarly journals Molecular Mechanisms of Phenolic‐Rich Botanical Drug Product‐Induced Apoptosis in Human Cancer Cell Lines

2007 ◽  
Vol 21 (5) ◽  
Author(s):  
Ali M Saboori ◽  
Premkala Prasanna ◽  
Selvi Krishanan ◽  
Negin Vatanian ◽  
Nandkishor B Managoli ◽  
...  
Keyword(s):  
Cell Lines ◽  
Cancer Cell ◽  
Molecular Mechanisms ◽  
Drug Product ◽  
Human Cancer ◽  
Cancer Cell Lines ◽  
Human Cancer Cell ◽  
Human Cancer Cell Lines ◽  
Botanical Drug ◽  
Induced Apoptosis

Cysteine cathepsins are not critical for TRAIL- and CD95-induced apoptosis in several human cancer cell lines

2012 ◽  
Vol 393 (12) ◽  
pp. 1417-1431 ◽  
Author(s):  
Aleš Špes ◽  
Barbara Sobotič ◽  
Vito Turk ◽  
Boris Turk
Keyword(s):  
Cell Lines ◽  
Broad Spectrum ◽  
Cathepsin B ◽  
Human Cancer ◽  
Human Cancer Cell ◽  
Human Cancer Cell Lines ◽  
Lysosomal Membrane Permeabilization ◽  
Cysteine Cathepsins ◽  
Cysteine Cathepsin ◽  
Induced Apoptosis

Abstract The potential role of cysteine cathepsins in tumor necrosis factor-related apoptosis-inducing ligand (TRAIL/Apo2L)- and CD95 (Fas/APO-1)-induced apoptosis was investigated using four different cell lines (HeLa, HuH-7, Jurkat, and U-937). All four cell lines exhibited different levels of cathepsins and responded differently to apoptosis triggering, with Jurkat cells being the most sensitive and the only ones that were sensitive to the agonistic anti-APO-1 antibody. Apoptosis was accompanied by caspase activation, loss of the mitochondria and lysosome integrity, and the release of cysteine cathepsins into the cytosol, as judged based on the hydrolysis of the cysteine cathepsin substrate benzyloxycarbonyl-Phe-Arg-7-amino-4-methylcoumarin and by the immunological detection of cathepsin B. The inhibition of caspases by the broad-spectrum inhibitor benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone prevented apoptosis, including the mitochondrial and lysosomal membrane permeabilization, as well as cathepsin release into the cytosol, consistent with caspases playing a crucial role in the process. Conversely, however, although the broad-spectrum cysteine cathepsin inhibitor (2S,3S)-trans-epoxysuccinyl-leucylamido-3-methyl-butane ethyl ester and the more cathepsin B-selective inhibitor [(2S,3S)-3-propylcarbamoyloxirane-2-carbonyl]-l-isoleucyl-l-proline methyl ester completely blocked cathepsin activity, these inhibitors neither prevented apoptosis and its progression nor the mitochondrial and lysosomal membrane permeabilization associated with this type of cell death. Consequently, cathepsin release into the cytosol was also not prevented. Together, these data indicate that cysteine cathepsins are not required for the TRAIL- and CD95-mediated apoptosis in various human cancer cell lines. This does not, however, rule out that lysosomes and cysteine cathepsins are involved in the amplification, but not in the initiation, of death receptor-mediated apoptosis in certain cell lines or under different stimulation conditions than the ones employed here.

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