Endoplasmic reticulum stress response (Unfolded protein response) (UPR)

The Endoplasmic Reticulum (ER) stress response, primarily mediated by the Unfolded Protein Response (UPR), is a cellular homeostatic mechanism activated when the protein-folding capacity of the ER is overwhelmed by the accumulation of misfolded proteins [Hetz et al., 2020, Nature Reviews Molecular Cell Biology]. In the context of oncology, tumor cells frequently hijack these survival pathways to adapt to harsh microenvironmental conditions such as hypoxia, nutrient deprivation, and acidic pH [Chen & Cubillos-Ruiz, 2021, Science]. The UPR consists of three main signaling branches initiated by the transmembrane sensors PERK (EIF2AK3), IRE1alpha (ERN1), and ATF6, which initially aim to restore homeostasis by attenuating translation and increasing chaperone production [Wang & Kaufman, 2016, Nature]. However, chronic or unresolved ER stress shifts the signaling toward pro-apoptotic pathways, primarily through the induction of CHOP (DDIT3), making these components attractive therapeutic targets [Oakes & Papa, 2015, Annual Review of Pathology]. Pharmacological modulation of the ER stress response aims to either inhibit the adaptive survival signals to sensitize tumors to chemotherapy or hyper-activate the terminal apoptotic phase to selectively eliminate cancer cells [Cubillos-Ruiz et al., 2017, Cell]. While promising, targeting these pathways presents challenges due to the essential role of the UPR in normal secretory cells, such as pancreatic beta cells and hepatocytes [Hetz & Papa, 2018, Molecular Cell].

Other names

Unfolded protein responseER stress responseProteotoxic stress responseTumor cell survival pathways and ER stress response

Modulation of the unfolded protein response (UPR) sensors to either inhibit adaptive survival mechanisms or promote terminal apoptosis in stressed cells.