p53-Mediated Oxidative Stress Enhances Indirubin-3′-Monoxime-Induced Apoptosis in HCT116 Colon Cancer Cells by Upregulating Death Receptor 5 and TNF-Related Apoptosis-Inducing Ligand Expression

Abstract

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 were 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 was promoted by p53-mediated ROS production. Our results also showed that I3M enhanced transcription factor C/EBP homologous protein (CHOP) expression, resulted in endoplasmic reticulum (ER) stress-mediated DR5 expression, which was upregulated by ROS production in HCT116 p53+/+ cells. Moreover, co-treatment with I3M and TRAIL enhanced 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 less sensitive to I3M-mediated apoptosis, suggesting that I3M could be a promising anti-cancer candidate against TRAIL-resistant p53+/+ cancer cells. Additionally, this study also revealed that I3M sensitizes colorectal cancer cells such as HT29 and SW480 to TRAIL-mediated apoptosis.

Physiological Overview of the Potential Link between the UPS and Ca2+ Signaling

“…The proteasome inhibitor bortezomib (BTZ) induces 5 -adenosine monophosphate (AMP)-activated protein kinase (AMPK) activation by increasing [Ca 2+ ] i and CaMKII subunit β in MDA-MB-231 and MDA-MB-498 cells [142]. Indirubin-3-monoxime (I3M, which enhances apoptosis through oxidative stress [143]) and curcumin are known anticancer components that induce cancer cell apoptosis [143,144]. These compounds induce paraptosis through mitochondrial Ca 2+ overload accompanied by proteasome impairment in malignant breast cancer cells [76,145].…”

Insight into the divergent role of TRAIL in non‐neoplastic neurological diseases

“…58 On the basis of this theory, various modulators, inducers and sensitizer of ROS were researched to enhance the sensitivity of TRAIL in a lot kinds of cancer cells, which is a promising research target towards TRAIL-related tumour drug resistance. 59,60 Conversely, in most cases, the primary task of the TRAIL-based therapeutics for CNS diseases is inhibiting the apoptotic pathway. Therefore, exploring an effective ROS inhibitor may be a novel and promising target compared with the traditional direct inhibition on TRAIL or In present America, more than 5 million residents were affected by AD and related financial burden reached $230 billion.…”