X-box Binding Protein 1 in Tumor Cell Adaptation and Death: Towards Specific Regulation

The ability to maintain homeostasis is critical for ensuring proper cell function and organismal viability. Environmental stress disrupts cell homeostasis by triggering molecular and metabolic changes leading to adaptation or death. Cells respond to environmental stress by activating stress- and compartment-specific response pathways. Unfolded protein response (UPR) is one of the stress response pathways that restore endoplasmic reticulum (ER) homeostasis during ER stress by regulation of protein refolding. Transcription factor X‐box binding protein 1 (XBP1s) plays a central role in cellular adaptation to ER stress by activation of multiple UPR target genes. Abnormal activity of XBP1s is harmful to cells and has been linked to tumor progression and metastasis. Currently, the targeting of XBP1 is considered a promising strategy for cancer treatment. However, UPR inhibitors are nonselective and decrease the XBP1s activity in normal cells leading to undesired effects of chemotherapy. Besides, the critical accumulation of XBP1s in the nucleus during prolonged ER stress stimulates the expression of transcription factor Krüppel-like factor 9 (KLF9), which induces increases in oxidants and calcium ion concentration and subsequent cell death. Because of differences in XBP1s transcriptional activity between normal and tumor cells, stimulation of UPR in a certain range can enhance oxidative stress and the effect of antitumor drugs in tumor cells and exhibit protective properties in the normal cells. This review discusses the mechanisms of cell adaptive and terminal responses based on transcriptional regulation by XBP1s and describes a biophysical model of dose-dependent biphasic response as a quantitative basis for specific regulation of XBP1s in normal and tumor cells.