Wu Bill X, Hong Feng, Zhang Yongliang, Ansa-Addo Ephraim, Li Zihai
Hollings Cancer Center, Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, South Carolina, USA.
Hollings Cancer Center, Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, South Carolina, USA.
Adv Cancer Res. 2016;129:165-90. doi: 10.1016/bs.acr.2015.09.001. Epub 2015 Sep 28.
As an endoplasmic reticulum heat-shock protein 90 (HSP90) paralog, GRP94 (glucose-regulated protein 94)/gp96 (hereafter referred to as GRP94) has been shown to be an essential master chaperone for multiple receptors including Toll-like receptors, Wnt coreceptors, and integrins. Clinically, expression of GRP94 correlates with advanced stage and poor survival in a variety of cancers. Recent preclinical studies have also revealed that GRP94 expression is closely linked to cancer growth and metastasis in melanoma, ovarian cancer, multiple myeloma, lung cancer, and inflammation-associated colon cancer. Thus, GRP94 is an attractive therapeutic target in a number of malignancies. The chaperone function of GRP94 depends on its ATPase domain, which is structurally distinct from HSP90, allowing design of highly selective GRP94-targeted inhibitors. In this chapter, we discuss the biology and structure-function relationship of GRP94. We also summarize the immunological roles of GRP94 based on the studies documented over the last two decades, as these pertain to tumorigenesis and cancer progression. Finally, the structure-based rationale for the design of selective small-molecule inhibitors of GRP94 and their potential application in the treatment of cancer are highlighted.
作为一种内质网热休克蛋白90（HSP90）旁系同源物，葡萄糖调节蛋白94（GRP94）/gp96（以下简称GRP94）已被证明是包括Toll样受体、Wnt共受体和整合素在内的多种受体的重要主伴侣蛋白。在临床上，GRP94的表达与多种癌症的晚期阶段和不良预后相关。最近的临床前研究还表明，GRP94的表达与黑色素瘤、卵巢癌、多发性骨髓瘤、肺癌以及炎症相关结肠癌的肿瘤生长和转移密切相关。因此，GRP94是多种恶性肿瘤中一个有吸引力的治疗靶点。GRP94的伴侣蛋白功能依赖于其ATP酶结构域，该结构域在结构上与HSP90不同，这使得设计高度选择性的GRP94靶向抑制剂成为可能。在本章中，我们讨论了GRP94的生物学特性及其结构-功能关系。我们还根据过去二十年的研究总结了GRP94在肿瘤发生和癌症进展方面的免疫作用。最后，强调了基于结构设计GRP94选择性小分子抑制剂的原理及其在癌症治疗中的潜在应用。
