Anticancer Strategy Targeting Cell Death Regulators: Switching the Mechanism of Anticancer Floxuridine-Induced Cell Death from Necrosis to Apoptosis

Cell death can be broadly characterized as either necrosis or apoptosis, depending on the morphological and biochemical features of the cell itself. We have previously reported that the treatment of mouse mammary carcinoma FM3A cells with the anticancer drug floxuridine (FUdR) induces necrosis in the original clone F28-7 but apoptosis in the variant F28-7-A. We have identified regulators, including heat shock protein 90, lamin-B1, cytokeratin-19, and activating transcription factor 3, of cell death mechanisms by using comprehensive gene and protein expression analyses and a phenotype-screening approach. We also observed that the individual inhibition or knockdown of the identified regulators in F28-7 results in a shift from necrotic to apoptotic morphology. Furthermore, we investigated microRNA (miRNA, miR) expression profiles in sister cell strains F28-7 and F28-7-A using miRNA microarray analyses. We found that several unique miRNAs, miR-351-5p and miR-743a-3p, were expressed at higher levels in F28-7-A than in F28-7. Higher expression of these miRNAs in F28-7 induced by transfecting miR mimics resulted in a switch in the mode of cell death from necrosis to apoptosis. Our findings suggest that the identified cell death regulators may play key roles in the decision of cell death mechanism: necrosis or apoptosis.

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Activating transcription factor-3 (ATF3) functions as a tumor suppressor in colon cancer and is up-regulated upon heat-shock protein 90 (Hsp90) inhibition

BMC Cancer ◽

10.1186/1471-2407-10-668 ◽

2010 ◽

Vol 10 (1) ◽

Cited By ~ 42

Author(s):

Christina Hackl ◽

Sven A Lang ◽

Christian Moser ◽

Akira Mori ◽

Stefan Fichtner-Feigl ◽

...

Keyword(s):

Colon Cancer ◽

Transcription Factor ◽

Heat Shock ◽

Tumor Suppressor ◽

Heat Shock Protein ◽

Heat Shock Protein 90 ◽

Activating Transcription Factor 3 ◽

Hsp90 Inhibition ◽

Activating Transcription Factor ◽

Transcription Factor 3

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Alterations in neuronal gene expression profiles in response to experimental demyelination and axonal transection

Multiple Sclerosis Journal ◽

10.1177/1352458509357063 ◽

2010 ◽

Vol 16 (3) ◽

pp. 303-316 ◽

Cited By ~ 1

Author(s):

G. Lovas ◽

JA Nielsen ◽

KR Johnson ◽

LD Hudson

Keyword(s):

Gene Expression ◽

Multiple Sclerosis ◽

Expression Profiles ◽

Gene Expression Profiles ◽

Neurological Deficits ◽

Activating Transcription Factor 3 ◽

Post Intervention ◽

Neuronal Gene ◽

Activating Transcription Factor ◽

Axonal Transection

The main pathological features of multiple sclerosis, demyelination and axonal transection, are considered to cause reversible and irreversible neurological deficits, respectively. This study aimed to separately analyze the effects of these pathological hallmarks on neuronal gene expression in experimental paradigms. The pontocerebellar pathway was targeted with either lysolecithin-induced chemical demyelination or a complete pathway transection (axonal transection) in rats. Transcriptional changes in the pontocerebellar neurons were investigated with microarrays at days 4, 10 and 37 post-intervention, which was confirmed by immunohistochemistry on protein level. A common as well as unique set of injury-response genes was identified. The increased expression of activating transcription factor 3 (Atf3) and thyrotropin-releasing hormone (Trh) in both injury paradigms was validated by immunohistochemistry. The expression of Atf3 in a patient with Marburg’s variant of multiple sclerosis was also detected, also confirming the activation of the Atf3 pathway in a human disease sample. It was concluded that this experimental approach may be useful for the identification of pathways that could be targeted for remyelinative or neuroprotective drug development.

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Stem cell-induced differential gene expression profiles associated with apoptosis, necrosis and anoikis: Novel insights into cell death mechanisms in prostate cancer

10.5505/2017ichc.op-15 ◽

2017 ◽

Author(s):

Cuneyd Parlayan

Keyword(s):

Gene Expression ◽

Prostate Cancer ◽

Cell Death ◽

Stem Cell ◽

Differential Gene Expression ◽

Expression Profiles ◽

Gene Expression Profiles ◽

Differential Gene ◽

Cell Death Mechanisms

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Coxsackievirus B3 modulates cell death by downregulating activating transcription factor 3 in HeLa cells

Virus Research ◽

10.1016/j.virusres.2007.05.007 ◽

2007 ◽

Vol 130 (1-2) ◽

pp. 10-17 ◽

Cited By ~ 8

Author(s):

Ha Young Hwang ◽

Joo-Young Kim ◽

Joong-Yeon Lim ◽

Sun-Ku Chung ◽

Jae-Hwan Nam ◽

...

Keyword(s):

Cell Death ◽

Transcription Factor ◽

Hela Cells ◽

Coxsackievirus B3 ◽

Activating Transcription Factor 3 ◽

Activating Transcription Factor ◽

Transcription Factor 3

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The spliceosome inhibitors isoginkgetin and pladienolide B induce ATF3-dependent cell death

10.1101/821363 ◽

2019 ◽

Author(s):

Erin J. Vanzyl ◽

Hadil Sayed ◽

Alex B. Blackmore ◽

Kayleigh R.C. Rick ◽

Pasan Fernando ◽

...

Keyword(s):

Cell Death ◽

Transcription Factor ◽

Apoptotic Cell ◽

Activating Transcription Factor 3 ◽

Genetic Determinants ◽

Pladienolide B ◽

Dependent Cell ◽

Activating Transcription Factor ◽

Cellular Stresses ◽

Mature Mrnas

AbstractThe spliceosome assembles on pre-mRNA in a stepwise manner through five successive pre-spliceosome complexes. The spliceosome functions to remove introns from pre-mRNAs to generate mature mRNAs that encode functional proteins. Many small molecule inhibitors of the spliceosome have been identified and they are cytotoxic. However, little is known about genetic determinants of cell sensitivity. Activating transcription factor 3 (ATF3) is a transcription factor that can stimulate apoptotic cell death in response to a variety of cellular stresses. Here, we used a genetic approach to determine if ATF3 was important in determining the sensitivity of mouse embryonic fibroblasts (MEFs) to two splicing inhibitors: pladienolide B (PB) and isoginkgetin (IGG), that target different pre-spliceosome complexes. Both compounds led to increased ATF3 expression and apoptosis in control MEFs while ATF3 null cells were significantly protected from the cytotoxic effects of these drugs. Similarly, ATF3 was induced in response to IGG and PB in the two human tumour cell lines tested while knockdown of ATF3 protected cells from both drugs. Taken together, ATF3 appears to contribute to the cytotoxicity elicited by these spliceosome inhibitors in both murine and human cells.

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The spliceosome inhibitors isoginkgetin and pladienolide B induce ATF3-dependent cell death

PLoS ONE ◽

10.1371/journal.pone.0224953 ◽

2020 ◽

Vol 15 (12) ◽

pp. e0224953

Author(s):

Erin J. Vanzyl ◽

Hadil Sayed ◽

Alex B. Blackmore ◽

Kayleigh R. C. Rick ◽

Pasan Fernando ◽

...

Keyword(s):

Cell Death ◽

Transcription Factor ◽

Apoptotic Cell ◽

Activating Transcription Factor 3 ◽

Genetic Determinants ◽

Pladienolide B ◽

Dependent Cell ◽

Activating Transcription Factor ◽

Cellular Stresses ◽

Mature Mrnas

The spliceosome assembles on pre-mRNA in a stepwise manner through five successive pre-spliceosome complexes. The spliceosome functions to remove introns from pre-mRNAs to generate mature mRNAs that encode functional proteins. Many small molecule inhibitors of the spliceosome have been identified and they are cytotoxic. However, little is known about genetic determinants of cell sensitivity. Activating transcription factor 3 (ATF3) is a transcription factor that can stimulate apoptotic cell death in response to a variety of cellular stresses. Here, we used a genetic approach to determine if ATF3 was important in determining the sensitivity of mouse embryonic fibroblasts (MEFs) to two splicing inhibitors: pladienolide B (PB) and isoginkgetin (IGG), that target different pre-spliceosome complexes. Both compounds led to increased ATF3 expression and apoptosis in control MEFs while ATF3 null cells were significantly protected from the cytotoxic effects of these drugs. Similarly, ATF3 was induced in response to IGG and PB in the two human tumour cell lines tested while knockdown of ATF3 protected cells from both drugs. Taken together, ATF3 appears to contribute to the cytotoxicity elicited by these spliceosome inhibitors in both murine and human cells.

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Combined Treatment of 5-Fluorouracil and Delta-Tocotrienol Induce of Apoptosis and Autophagy in Colorectal Cancer Cells

Journal of Global Oncology ◽

10.1200/jgo.18.82200 ◽

2018 ◽

Vol 4 (Supplement 2) ◽

pp. 203s-203s ◽

Cited By ~ 1

Author(s):

S.Y. Tham ◽

C.W. Mai ◽

J.Y. Fu ◽

H.-S. Loh

Keyword(s):

Colorectal Cancer ◽

Cell Death ◽

Cancer Cells ◽

Treatment Approach ◽

Expression Profiles ◽

Combined Treatment ◽

High Dose ◽

First Choice ◽

Colorectal Cancer Cells ◽

The Individual

Background: 5-fluorouracil (5-FU) has been a first choice chemotherapeutic drug used to treat colorectal cancer. However, its therapeutic outcome often be limited by high-dose toxicities and drug resistance development. Hence, the current research advocates combined application of delta-tocotrienol (δ-T3), as a natural chemosensitizer, with 5-FU as a novel treatment approach for colorectal cancer. Aim: To investigate the combinatorial anticancer effects of δ-T3 and 5-FU on colorectal cancer cell lines. Methods: Cell viability assay was performed to investigate the individual and combined effects of δ-T3 (0.1-100 µM) and 5-FU (0.1-100 µM) on HCT116, HCC2998, Caco-2 and SW48 colorectal cancer cells at 72 h. Subsequently, the synergistic combination were evaluated for the effects on clonogenicity, apoptosis and autophagy. Morphologic assessment was conducted by bright-field and fluorescence microscopy. The protein expression profiles of programmed cell death and survival markers were determined by Western blotting. Results: Combined treatment of subeffective dose of δ-T3 significantly lowered the IC50 of 5-FU in Caco-2 and SW48 colorectal adenocarcinomas for 16-fold and fourfold respectively, signifying a chemosensitising effect. Clonogenic survival assay showed that the combined treatment profoundly hampered the cell survival as compared with the individual single treatments. Apoptosis was induced by the combined treatment as confirmed by flow cytometry. Interestingly, both apoptotic and autophagic morphologies were observed, including nuclear condensation, cell shrinkage, cytoplasmic vacuolation and extension. The presence of autophagy was further confirmed by increase LC3A/B ratio and high volume of acidic vesicular organelles. The combined treatment were found to upregulate prodeath proteins such as Bax, caspase-8, caspase-3, PARP and downregulate prosurvival proteins such as cIAP, XIAP and survivin. Conclusion: The enhanced cell death induced by 5-FU and δ-T3 combined treatment involved both apoptosis and autophagy, suggesting a novel and effective treatment approach for colorectal cancer.

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