Unleashing the full potential of Hsp90 inhibitors as cancer therapeutics through simultaneous inactivation of Hsp90, Grp94, and TRAP1

Hye-Kyung Park,Sung Hu,Sora Yoon,Nam Gu Yoon,So Yeon Kim,Ji-Eun Lee,Young Chan Chae,Dougu Nam,Jun-Hee Hong,Byoung Heon Kang,Jong Bae Park

doi:10.1038/s12276-019-0360-x

Abstract

The Hsp90 family proteins Hsp90, Grp94, and TRAP1 are present in the cell cytoplasm, endoplasmic reticulum, and mitochondria, respectively; all play important roles in tumorigenesis by regulating protein homeostasis in response to stress. Thus, simultaneous inhibition of all Hsp90 paralogs is a reasonable strategy for cancer therapy. However, since the existing pan-Hsp90 inhibitor does not accumulate in mitochondria, the potential anticancer activity of pan-Hsp90 inhibition has not yet been fully examined in vivo. Analysis of The Cancer Genome Atlas database revealed that all Hsp90 paralogs were upregulated in prostate cancer. Inactivation of all Hsp90 paralogs induced mitochondrial dysfunction, increased cytosolic calcium, and activated calcineurin. Active calcineurin blocked prosurvival heat shock responses upon Hsp90 inhibition by preventing nuclear translocation of HSF1. The purine scaffold derivative DN401 inhibited all Hsp90 paralogs simultaneously and showed stronger anticancer activity than other Hsp90 inhibitors. Pan-Hsp90 inhibition increased cytotoxicity and suppressed mechanisms that protect cancer cells, suggesting that it is a feasible strategy for the development of potent anticancer drugs. The mitochondria-permeable drug DN401 is a newly identified in vivo pan-Hsp90 inhibitor with potent anticancer activity.

Highlights

Heat shock protein 90 (Hsp90) family members are ATP-dependent molecular chaperones that regulate the stability and function of client proteins involved in growth, survival, and adaptation of cancer cells to cellular stress[1,2,3]
Hsp[90] family proteins comprise four paralogs, each of which resides at different subcellular locations: Hsp90α/β in the cytoplasm, glucose-regulated protein 94 (Grp94) in the endoplasmic reticulum (ER), and tumor necrosis factor receptor-associated protein-1 (TRAP1) in mitochondria
Consistent with this, we found that increases in cytoplasmic calcium in HeLa cells were markedly reduced after genetic knockdown of either cyclophilin D (CypD) or ryanodine receptor 2 (RyR2) (Fig. 4e, f)

Summary

Introduction

Heat shock protein 90 (Hsp90) family members are ATP-dependent molecular chaperones that regulate the stability and function of client proteins involved in growth, survival, and adaptation of cancer cells to cellular stress[1,2,3]. Hsp[90] family proteins comprise four paralogs, each of which resides at different subcellular locations: Hsp90α/β in the cytoplasm, glucose-regulated protein 94 (Grp94) in the endoplasmic reticulum (ER), and tumor necrosis factor receptor-associated protein-1 (TRAP1) in mitochondria. Simultaneous inactivation of all Hsp[90] family proteins can compromise multiple tumorigenic pathways operating in different cellular compartments; this approach is very likely to increase anticancer activity above that afforded by paralog-specific inactivation of Hsp[90] family proteins. Many Hsp[90] inhibitors targeting the ATP binding pocket exhibited cross-reactivity against both Grp[94] and TRAP1 in vitro; such agents are known as pan-Hsp[90] inhibitors[11]. The reported cellular activity of most Hsp[90] inhibitors originates primarily from inactivation of cytosolic and/or ER Hsp[90] paralogs, not from

Methods

Results

Conclusion