Endoplasmic reticulum stress and unfolded protein response pathway (UPR)

The Unfolded Protein Response (UPR) is a complex intracellular signaling network activated by endoplasmic reticulum (ER) stress, a condition where misfolded proteins accumulate in the ER lumen. In the context of oncology, tumor cells frequently encounter ER stress due to intrinsic factors like oncogene activation and extrinsic factors such as hypoxia and nutrient scarcity. The UPR initially serves a cytoprotective role by enhancing protein folding capacity and reducing translation, thereby promoting tumor cell survival, metastasis, and chemoresistance. However, if ER stress is severe or persistent, the UPR can transition from a pro-survival to a pro-apoptotic program, primarily through the induction of CHOP. Therapeutic interventions target key UPR sensors—IRE1α, PERK, and ATF6—to either disrupt survival signaling or push cells toward terminal apoptosis, offering a strategy to overcome drug resistance and improve patient outcomes.

Other names

UPR pathwayER stress responseEndoplasmic reticulum stress and unfolded protein response pathways in tumor cellsER stress signaling

Modulation of ER stress sensors (IRE1α, PERK, ATF6) and chaperones (GRP78/BiP) to either inhibit pro-survival signaling or exacerbate stress to trigger terminal apoptosis in tumor cells.