Kidney Disease Research Group, UQ Diamantina Institute, Translational Research Institute, The University of Queensland, 37 Kent Street, Woolloongabba, Brisbane, 4102, Australia.
Department of Nephrology, Princess Alexandra Hospital, Woolloongabba, Brisbane, Australia.
Cell Stress Chaperones. 2018 May;23(3):317-334. doi: 10.1007/s12192-017-0844-3. Epub 2017 Sep 27.
Although there have been advances in our understanding of carcinogenesis and development of new treatments, cancer remains a common cause of death. Many regulatory pathways are incompletely understood in cancer development and progression, with a prime example being those related to the endoplasmic reticulum (ER). The pathological sequelae that arise from disruption of ER homeostasis are not well defined. The ER is an organelle that is responsible for secretory protein biosynthesis and the quality control of protein folding. The ER triggers an unfolded protein response (UPR) when misfolded proteins accumulate, and while the UPR acts to restore protein folding and ER homeostasis, this response can work as a switch to determine the death or survival of cells. The treatment of cancer with agents that target the UPR has shown promising outcomes. The UPR has wide crosstalk with other signaling pathways. Multi-targeted cancer therapies which target the intersections within signaling networks have shown synergistic tumoricidal effects. In the present review, the basic cellular and signaling pathways of the ER and UPR are introduced; then the crosstalk between the ER and other signaling pathways is summarized; and ultimately, the evidence that the UPR is a potential target for cancer therapy is discussed. Regulation of the UPR downstream signaling is a common therapeutic target for different tumor types. Tumoricidal effects achieved from modulating the UPR downstream signaling could be enhanced by phosphodiesterase 5 (PDE5) inhibitors. Largely untapped by Western medicine for cancer therapies are Chinese herbal medicines. This review explores and discusses the value of some Chinese herbal extracts as PDE5 inhibitors.
尽管我们对癌症的发生和新治疗方法的发展有了更多的了解，但癌症仍然是常见的死亡原因。许多监管途径在癌症的发展和进展中还不完全了解，其中一个主要例子是与内质网（ER）相关的途径。内质网是一种负责分泌蛋白生物合成和蛋白质折叠质量控制的细胞器。当错误折叠的蛋白质积累时，内质网会引发未折叠蛋白反应（UPR），虽然 UPR 旨在恢复蛋白质折叠和内质网平衡，但这种反应可以作为决定细胞死亡或存活的开关。用靶向 UPR 的药物治疗癌症已显示出有希望的结果。UPR 与其他信号通路广泛相互作用。靶向信号网络交叉点的多靶点癌症疗法已显示出协同的杀瘤作用。在本综述中，介绍了 ER 和 UPR 的基本细胞和信号通路；然后总结了 ER 与其他信号通路之间的串扰；最终讨论了 UPR 作为癌症治疗潜在靶点的证据。调节 UPR 下游信号是不同肿瘤类型的常见治疗靶点。通过调节 UPR 下游信号获得的杀瘤作用可以通过磷酸二酯酶 5（PDE5）抑制剂增强。中药在癌症治疗方面尚未被西方医学充分利用。本综述探讨并讨论了一些中药提取物作为 PDE5 抑制剂的价值。
