Ixazomib promotes CHOP-dependent DR5 induction and apoptosis in colorectal cancer cells

Abstract

Background: Ixazomib (Ninlaro), a novel proteasome inhibitor, has been developed for the treatment of many cancers and has demonstrated anti-tumor efficacy against various malignancies. However, the mechanism of the anti-tumor effect of ixazomib in colorectal cancer (CRC) cells remains unclear. Methods: MTS and flow cytometry were performed to determine the effect of ixazomib on CRC cells. Western blotting and real-time RT-PCR were performed to detect ixazomib-induced DR5 upregulation. ChIP was performed to detect CHOP binding to DR5 promoter. Finally, xenograft experiments were carried out to measure the antitumor effect of ixazomib in vivo. Results: In this study, we revealed the mechanism by which ixazomib inhibits the growth of CRC cells. Our findings indicated that ixazomib treatment induces CHOP-dependent DR5 induction, irrespective of p53 status. Furthermore, DR5 is necessary for ixazomib-mediated apoptosis. Ixazomib also synergized with TRAIL to induce marked apoptosis via DR5 in CRC cells. Conclusions: Our findings further suggested that ixazomib sensitizes TRAIL/death receptor signaling pathway-targeted CRC and suggested that DR5 induction could be a valuable indicator of ixazomib sensitivity.

Ixazomib Induces Apoptosis and Suppresses Proliferation in Esophageal Squamous Cell Carcinoma through Activation of the c-Myc/NOXA Pathway

“…Therefore, inducing ubiquitinated protein accumulation has become an increasingly important treatment strategy in cancer therapy, proteasome inhibitors have been reported to have significant antitumor activity against various cancer cells through this mechanism (Sato et al, 2012;Sato et al, 2014;Sato et al, 2017). The novel orally proteasome inhibitor ixazomib is currently used for treatment of multiple myeloma patients, and it has been confirmed to have killing efficiency to tumor cells (Sato et al, 2017;Yue and Sun, 2019;Harris et al, 2020). In this study, we explore whether proteasome inhibitor ixazomib have therapeutic effects on ESCC.…”

“…Other scholars also reported that c-Myc was a prime transcription factor to transactivate NOXA (Nikiforov et al, 2007). A series of studies have shown that proteasome inhibitor bortezomib can induce c-Myc-dependent up-regulation of NOXA, leading to apoptosis in colorectal and pancreatic cancer cells (Yue and Sun, 2019;Lankes et al, 2020).…”

“…Currently, ixazomib was approved for treatment of multiple myeloma patient combination with lenalidomide and dexamethasone by the US FDA (Shirley, 2016). Besides haematological neoplasms, a series of studies have suggested that ixazomib also have therapeutic anticancer functions in solid tumor, including colorectal cancer, bladder cancer, osteosarcoma and breast cancer (Kupperman et al, 2010;Sato et al, 2017;Yue and Sun, 2019;Harris et al, 2020). However, the detailed mechanisms underlying ixazomib induced cancer cell death remain unclear.…”

Curcumol Overcomes TRAIL Resistance of Non‐Small Cell Lung Cancer by Targeting NRH:Quinone Oxidoreductase 2 (NQO2)

“…This finding provides a clue for developing TRAIL‐sensitizing agents. Many ROS inducers, such as thapsigargin, [ 37 ] proteasome inhibitors (MG132 and ninlaro), [ 38 ] and phytocompounds [ 39 ] were reported to exhibit anticancer effects in combination with TRAIL. However, their stability and safety for the clinical application remain to be the obstacle.…”

ROS‐mediated PERK‐eIF2α‐ATF4 pathway plays an important role in arsenite‐induced L‐02 cells apoptosis via regulating CHOP‐DR5 signaling

“…Therefore, the appropriative level of ER stress defines a time window for adaptation and unmitigated ER stress commits the cells to an apoptosis fate. C/EBP homologous protein (CHOP) is considered to be a critical marker of ER stress‐medicated switch from pro survival to pro apoptosis, largely because of as an inducer of death receptor 5 (DR5) transcription 25,26 …”