Abstract
Polyphenols have been shown to possess several beneficial properties, including properties involved in the prevention or treatment of cancer. Among these polyphenols, a leading role is played by dihydroxyphenylethanol (DPE), the most powerful antioxidant compound contained in the olive oil. DPE has been previously reported to induce endoplasmic reticulum (ER) stress and to reduce cell survival in colon cancer, one of the most common and aggressive cancers in developed countries. In this study, we further investigated the activation of UPR by DPE and explored the roles of the three UPR sensors, inositol-requiring enzyme (IRE) 1 alpha, protein kinase RNA-like endoplasmic reticulum kinase (PERK), and activating transcription factor (ATF6), in the cell death–survival decision of wt and mutp53 colon cancer cells and the underlying mechanisms involved. We also unveiled a new interplay between ATF6 and wt, as well as mutp53, which may have important implications in cancer therapy.
Highlights
The unfolded protein response (UPR) is a defense mechanism that helps cells to face endoplasmic reticulum (ER) stress
RKO wtp53 and SW480 mutp53 colon cancer cells were treated with different doses of DPE (50 and 100 μM) for 24 and 48 h, cell survival and proliferation were evaluated via trypan blue and MTT assays, respectively
We explored UPR sensor activation and its role in the cytotoxic effect of DPE against wt and mutp53 colon cancer cells
Summary
The unfolded protein response (UPR) is a defense mechanism that helps cells to face endoplasmic reticulum (ER) stress. Its binding to the three UPR sensors, namely inositol-requiring enzyme (IRE) 1 alpha, protein kinase RNA-like endoplasmic reticulum kinase (PERK), and activating transcription factor (ATF6), maintains them in an inactive state. When unfolded or misfolded proteins accumulate in the ER causing ER stress, they attract BiP and detach it from UPR sensors, resulting in UPR activation [1]. The intensity and duration of ER stress dictate the outcome of UPR in terms of cell survival or death, as it may promote pro-survival processes such as protein degradation and protein translation inhibition, it may upregulate chaperones such as BiP, or in cases of mild stress it may lead to an increased expression of CHOP and apoptosis, such as when the protective capacities of UPR are overwhelmed.
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