Links between the unfolded protein response and the DNA damage response in hypoxia: a systematic review

Abstract

Hypoxia is a feature of most solid tumours and predicts for poor prognosis. In radiobiological hypoxia (<0.1% O2) cells become up to three times more resistant to radiation. The biological response to radiobiological hypoxia is one of few physiologically relevant stresses that activates both the unfolded protein and DNA damage responses (UPR and DDR). Links between these pathways have been identified in studies carried out in normoxia. Based in part on these previous studies and recent work from our laboratory, we hypothesised that the biological response to hypoxia likely includes overlap between the DDR and UPR. While inhibition of the DDR is a recognised strategy for improving radiation response, the possibility of achieving this through targeting the UPR has not been realised. We carried out a systematic review to identify links between the DDR and UPR, in human cell lines exposed to <2% O2. Following PRISMA guidance, literature from January 2010 to October 2020 were retrieved via Ovid MEDLINE and evaluated. A total of 202 studies were included. LAMP3, ULK1, TRIB3, CHOP, NOXA, NORAD, SIAH1/2, DYRK2, HIPK2, CREB, NUPR1, JMJD2B, NRF2, GSK-3B, GADD45a, GADD45b, STAU1, C-SRC, HK2, CAV1, CypB, CLU, IGFBP-3 and SP1 were highlighted as potential links between the hypoxic DDR and UPR. Overall, we identified very few studies which demonstrate a molecular link between the DDR and UPR in hypoxia, however, it is clear that many of the molecules highlighted warrant further investigation under radiobiological hypoxia as these may include novel therapeutic targets to improve radiotherapy response.

Zinc Supplementation Enhances the Pro-Death Function of UPR in Lymphoma Cells Exposed to Radiation

“…The apoptotic effect was confirmed by annexin V staining that increased in BC3 cells, particularly following Zinc/radiation treatment ( Figure 3 C). ER stress/UPR activation have been shown to influence DNA repair following treatment with genotoxic agents [ 27 ]; therefore, next we investigated whether Zinc-enhanced cell death could correlate with increased DNA damage in cells exposed to low-dose radiation. At this aim we assessed the appearance of the phosphorylated form of H2AX ( γ H2AX) and, as shown in Figure 3 D,G, we found that radiation increased γ H2AX and that it further increased with Zinc/radiation combination.…”

Interconnected Adaptive Responses: A Way Out for Cancer Cells to Avoid Cellular Demise

“…It is particularly important to assess the impact of each UPR sensor on DDR molecules in order to design the most appropriate combination therapies able to counteract the mechanisms that allow cancer cells to survive, despite the exposure to anti-cancer treatments. Interestingly, some molecules belonging to UPR, besides ER stress, can be activated by DNA damage [ 61 ]. For example, ATF4, a transcription factor involved in the up-regulation of the pro-apoptotic molecule CHOP, can be activated by both UPR and DDR signaling.…”

Cell Death and Survival Pathways Involving ATM Protein Kinase

“…DNA damaging stimuli such as UV, IR and exposure to chemicals can also damage cellular proteins. Therefore, DNA damage is often associated with ER stress, which elicits the subsequent unfolded protein response (UPR) in stressed cells [33]. Like DDR, UPR can result not only in cellular protection by facilitating the degradation of misfolded proteins, but also in the induction of apoptosis when cellular stresses surpass the cellular repair capacity [34,35].…”