Nyberg William A, Espinosa Alexander
Unit of Experimental Rheumatology, Center for Molecular Medicine, L8:04, Karolinska University Hospital, Karolinska Institutet, Sjukhusringen 6, SE-171 76, Stockholm, Sweden.
Unit of Experimental Rheumatology, Center for Molecular Medicine, L8:04, Karolinska University Hospital, Karolinska Institutet, Sjukhusringen 6, SE-171 76, Stockholm, Sweden.
Biochem Biophys Res Commun. 2016 May 13;473(4):789-794. doi: 10.1016/j.bbrc.2016.03.080. Epub 2016 Mar 19.
Endoplasmic reticulum (ER) stress is a physiological response to protein overload or misfolded proteins in the ER. Certain anti-cancer drugs, e.g. bortezomib and nelfinavir, induce ER stress implying that this could be a successful therapeutic strategy against several forms of cancer. To find novel ER-stress inducers we screened a panel of natural and synthetic Toll-like receptor (TLR) agonists against human keratinocytes and identified the anti-cancer drug imiquimod (IMQ) as a potent inducer of ER stress. Other TLR7 and TLR8 agonists, including resiquimod and gardiquimod, did not induce ER stress, demonstrating that IMQ induces ER stress independently of TLR7 and TLR8. We further confirmed this by showing that IMQ could still induce ER stress in mouse Tlr7(-/-) cells. IMQ also induced a rapid and transient influx of extracellular Ca(2+) together with the release of Ca(2+) from internal stores. Depletion of Ca(2+) from the ER is a known cause of ER stress suggesting that IMQ induces ER stress via depletion of ER Ca(2+). The ER-stress inducing property of IMQ is possibly of importance for its efficacy in treating basal cell carcinoma, in situ melanoma, and squamous cell carcinoma. Our data could potentially be harnessed for rational design of even more potent ER-stress inducers and new anti-cancer drugs.
内质网（ER）应激是内质网对蛋白质过载或错误折叠蛋白的一种生理反应。某些抗癌药物，如硼替佐米和奈非那韦，可诱导内质网应激，这意味着这可能是一种针对多种癌症的成功治疗策略。为了寻找新型内质网应激诱导剂，我们针对人角质形成细胞筛选了一组天然和合成的Toll样受体（TLR）激动剂，并确定抗癌药物咪喹莫特（IMQ）是一种有效的内质网应激诱导剂。其他TLR7和TLR8激动剂，包括瑞喹莫德和加地喹莫德，均未诱导内质网应激，这表明IMQ独立于TLR7和TLR8诱导内质网应激。我们通过证明IMQ仍可在小鼠Tlr7（-/-）细胞中诱导内质网应激进一步证实了这一点。IMQ还诱导细胞外Ca（2+）迅速短暂内流，同时伴有内质网中Ca（2+）的释放。内质网Ca（2+）耗竭是内质网应激的已知原因，这表明IMQ通过内质网Ca（2+）耗竭诱导内质网应激。IMQ的内质网应激诱导特性可能对其治疗基底细胞癌、原位黑色素瘤和鳞状细胞癌的疗效具有重要意义。我们的数据可能有助于合理设计更有效的内质网应激诱导剂和新型抗癌药物。
