Enhanced extrinsic apoptosis of therapy-induced senescent cancer cells using a death receptor 5 (DR5) selective agonist

Indirubin-3′-monoxime (I3M) exhibits anti-proliferative activity in various cancer cells; however, its anti-cancer mechanism remains incompletely elucidated. This study revealed that I3M promotes the expression of death receptor 5 (DR5) and tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) in HCT116 p53+/+ cells, resulting in caspase-mediated apoptosis. However, this study demonstrated that HCT116 p53-/- cells are insensitive to I3M-mediated apoptosis, indicating that I3M-induced apoptosis depends on the p53 status of HCT116 cells. Additionally, in HCT116 p53-/- cells, I3M significantly increased Ras expression, while in HCT116 p53+/+ cells, it reduced Ras expression. Furthermore, I3M remarkably increased the production of reactive oxygen species (ROS), which were reduced in transient p53 knockdown, indicating that I3M-mediated apoptosis is promoted by p53-mediated ROS production. Our results also showed that I3M enhanced transcription factor C/EBP homologous protein (CHOP) expression, resulting in endoplasmic reticulum (ER) stress-mediated DR5 expression, which is upregulated by ROS production in HCT116 p53+/+ cells. Moreover, co-treatment with TRAIL synergistically enhanced I3M-induced DR5 expression, thereby triggering TRAIL-induced apoptosis of HCT116 p53+/+ cells, which was interfered by a DR5-specific blocking chimeric antibody. In summary, I3M potently enhances TRAIL-induced apoptosis by upregulating DR5 expression via p53-mediated ROS production in HCT116 p53+/+ cells. However, HCT116 p53-/- cells were resistant to I3M-mediated apoptosis, suggesting that I3M could be a promising anti-cancer candidate against TRAIL-resistant p53+/+ cancer cells.

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Myeloid zinc finger 1 mediates sulindac sulfide-induced upregulation of death receptor 5 of human colon cancer cells

Scientific Reports ◽

10.1038/srep06000 ◽

2014 ◽

Vol 4 (1) ◽

Cited By ~ 7

Author(s):

Mano Horinaka ◽

Tatsushi Yoshida ◽

Mitsuhiro Tomosugi ◽

Shusuke Yasuda ◽

Yoshihiro Sowa ◽

...

Keyword(s):

Colon Cancer ◽

Cancer Cells ◽

Death Receptor ◽

Human Colon ◽

Death Receptor 5 ◽

Colon Cancer Cells ◽

Human Colon Cancer ◽

Sulindac Sulfide ◽

Myeloid Zinc Finger ◽

Human Colon Cancer Cells

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Up-regulation of Death Receptor 5/TRAIL-R2 Mediates Apoptosis Induced by N,N’-[(3,4-dimethoxyphenyl)methylene] Biscinnamide in Cancer Cells

Anticancer Research ◽

10.21873/anticanres.14506 ◽

2020 ◽

Vol 40 (9) ◽

pp. 5035-5041

Author(s):

HIROMI ◽

SUSUMU NAKATA ◽

JUN'ICHI UENISHI

Keyword(s):

Cancer Cells ◽

Death Receptor ◽

Death Receptor 5

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Artemisinin Derivatives Stimulate DR5-Specific TRAIL-Induced Apoptosis by Regulating Wildtype P53

Cancers ◽

10.3390/cancers12092514 ◽

2020 ◽

Vol 12 (9) ◽

pp. 2514

Author(s):

Xinyu Zhou ◽

Sietske N. Zijlstra ◽

Abel Soto-Gamez ◽

Rita Setroikromo ◽

Wim J. Quax

Keyword(s):

Colon Cancer ◽

Cancer Cells ◽

Death Receptor ◽

Dependent Manner ◽

Death Receptor 5 ◽

Novel Therapy ◽

Artemisinin Derivatives ◽

The Status ◽

Cervical Cancer Cells ◽

Induced Apoptosis

Artemisinin derivatives, widely known as commercial anti-malaria drugs, may also have huge potential in treating cancer cells. It has been reported that artemisinin derivatives can overcome resistance to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis in liver and cervical cancer cells. In our study, we demonstrated that artesunate (ATS) and dihydroartemisinin (DHA) are more efficient in killing colon cancer cells compared to artemisinin (ART). ATS/DHA induces the expression of DR5 in a P53 dependent manner in HCT116 and DLD-1 cells. Both ATS and DHA overcome the resistance to DHER-induced apoptosis in HCT116, mainly through upregulating death receptor 5 (DR5). We also demonstrate that DHA sensitizes HCT116 cells to DHER-induced apoptosis via P53 regulated DR5 expression in P53 knockdown assays. Nevertheless, a lower effect was observed in DLD-1 cells, which has a single Ser241Phe mutation in the P53 DNA binding domain. Thus, the status of P53 could be one of the determinants of TRAIL resistance in some cancer cells. Finally, the combination treatment of DHA and the TRAIL variant DHER increases cell death in 3D colon cancer spheroid models, which shows its potential as a novel therapy.

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