Medical Cell Biology, Uppsala University, 751 05 Uppsala, Sweden.
Pharmaceutical Biosciences, Uppsala University, 751 05 Uppsala, Sweden.
Cells. 2022 Feb 11;11(4):632. doi: 10.3390/cells11040632.
Hepatocellular carcinoma (HCC) is one of the most common and deadly cancers worldwide. It is usually diagnosed in an advanced stage and is characterized by a high intrinsic drug resistance, leading to limited chemotherapeutic efficacy and relapse after treatment. There is therefore a vast need for understanding underlying mechanisms that contribute to drug resistance and for developing therapeutic strategies that would overcome this. The rapid proliferation of tumor cells, in combination with a highly inflammatory microenvironment, causes a chronic increase of protein synthesis in different hepatic cell populations. This leads to an intensified demand of protein folding, which inevitably causes an accumulation of misfolded or unfolded proteins in the lumen of the endoplasmic reticulum (ER). This process is called ER stress and triggers the unfolded protein response (UPR) in order to restore protein synthesis or-in the case of severe or prolonged ER stress-to induce cell death. Interestingly, the three different arms of the ER stress signaling pathways have been shown to drive chemoresistance in several tumors and could therefore form a promising therapeutic target. This review provides an overview of how ER stress and activation of the UPR contributes to drug resistance in HCC.
肝细胞癌 (HCC) 是全球最常见和最致命的癌症之一。它通常在晚期诊断，其特征是内在药物耐药性高，导致化疗效果有限且治疗后复发。因此，人们迫切需要了解导致耐药性的潜在机制，并开发克服这种耐药性的治疗策略。肿瘤细胞的快速增殖，加上高度炎症的微环境，导致不同肝实质细胞群体的蛋白质合成慢性增加。这导致蛋白质折叠的需求加剧，不可避免地导致内质网 (ER) 腔中错误折叠或未折叠的蛋白质积累。这个过程称为内质网应激，并触发未折叠蛋白反应 (UPR)，以恢复蛋白质合成，或在严重或持久的内质网应激情况下，诱导细胞死亡。有趣的是，内质网应激信号通路的三个不同分支已被证明可导致多种肿瘤的化疗耐药性，因此可能成为有前途的治疗靶点。本综述概述了内质网应激和 UPR 的激活如何导致 HCC 中的耐药性。
