Role of Activating Transcription Factor 3 (ATF3) in Endoplasmic Reticulum (ER) Stress-induced Sensitization of p53-deficient Human Colon Cancer Cells to Tumor Necrosis Factor (TNF)-related Apoptosis-inducing Ligand (TRAIL)-mediated Apoptosis through Up-regulation of Death Receptor 5 (DR5) by Zerumbone and Celecoxib

Abstract

Background: Death receptor 5 (DR5) triggers cell death upon binding to its ligand TRAIL. Results: ATF3 promotes DR5 induction and apoptotic cell death upon zerumbone or celecoxib treatment in human p53-deficient colorectal cancer cells. Conclusion: ATF3 is an essential transcription factor for p53-independent DR5 induction through the ROS-ER stress pathway. Significance: ATF3 may be a useful biomarker for TRAIL-based anticancer therapy.

Derlin-1 is overexpressed in human colon cancer and promotes cancer cell proliferation

“…Previous research has shown that Derlin-1 is overexpressed in human breast carcinoma and protects the cancer cells from ER stressinduced apoptosis [6]. Almost all solid tumors including colon cancer encounter ER stress, such as hypoxia, and tumor growth depends on an intact unfolded protein response (UPR) [17][18][19][20][21]. Furthermore, Derlin-1 expression has been shown to be upregulated by inducers of ER stress and Derlin-1 reportedly mediates retrotranslocation of misfolded proteins from ER lumen into the cytosol [3,[22][23][24].…”

Physiological/pathological ramifications of transcription factors in the unfolded protein response

“…ATF3 also increases expression of MDM2 to facilitate MMP-2 degradation and subsequent inhibition of cell invasion in esophageal squamous cell carcinoma . In colorectal cancer, ATF3 activates DR5 to enhance sensitivity to apoptotic cell death (Taketani et al 2012;Edagawa et al 2014). In addition, bone morphogenetic protein (BMP) signaling activates ATF3 to bind open chromatin structures at AP1-preloaded sites and inhibit the oncogenic network (Gargiulo et al 2013).…”

Endoplasmic reticulum proteostasis in glioblastoma—From molecular mechanisms to therapeutic perspectives

“…2). The C/EBP homologous protein (CHOP) is a major proapoptotic transcription factor triggered by UPR that suppresses antiapoptotic outer mitochondrial membrane protein BCL2 (B cell lymphoma 2) and induces proapoptotic proteins such as death receptor 5 (DR5) and ER oxidoreductinlike protein 1a (ERO1a) (61)(62)(63)(64). In GBM cell culture models, numerous anticancer drugs were shown to induce CHOP expression.…”