Extracellular Hsp90 (eHsp90) as the Actual Target in Clinical Trials

Abstract

Despite extensive investigative studies and clinical trials over the past two decades, we still do not understand why cancer cells are more sensitive to the cellular toxicity of Hsp90 inhibitors than normal cells. We still do not understand why only some cancer cells are sensitive to the Hsp90 inhibitors. Based on studies of the past few years, we argue that the selected sensitivity of cancer cells to Hsp90 inhibitors, such as 17-N-allylamino-17-demethoxygeldanamycin, is due to inhibition of the extracellular Hsp90 (eHsp90) rather than intracellular Hsp90 by these inhibitors. Because not all tumor cells utilize eHsp90 for motility, invasion and metastasis, only the group of “eHsp90-dependent” cancer cells is sensitive to Hsp90 inhibitors. If these notions prove to be true, pharmaceutical agents that selectively target eHsp90 should be more effective on tumor cells and less toxic on normal cells than current inhibitors that nondiscriminatively target both extracellular and intracellular Hsp90.

Extracellular Heat Shock Protein 90 Signals through Subdomain II and the NPVY Motif of LRP-1 Receptor to Akt1 and Akt2: a Circuit Essential for Promoting Skin Cell Migration In Vitro and Wound Healing In Vivo

“…During skin wound healing, eHsp90␣ drives migration of keratinocytes, dermal fibroblasts, and endothelial cells into the wound bed to promote wound closure (9,10). In tumor progression, eHsp90␣ adds invasion and metastasis of the tumor cells (7,16,18,27,28). However, despite the understanding of eHsp90␣ function in both physiological and pathological processes, the mechanism by which eHsp90␣ promotes cell migration remained elusive.…”

“…Another group of studies argued that eHsp90␣ no longer functions as a chaperone protein. Instead, it acts as a ligand, via its F-5 domain, that binds to the cell surface receptor, LRP-1, and triggers cross-membrane signaling to execute its promotility function (6,7). The relationships between the "extracellular chaperone" and "extracellular signaling" mechanisms remain to be established.…”

“…Inside the cell, Hsp90 proteins act as an ATPase-dependent chaperone that binds and protects hundreds of client proteins from misfolding, structural damage, or protease degradation triggered by environmental insults or pathological stress (1)(2)(3)(4). For the past 10 years, in particular, studies have convincingly made it clear that the same stress signals can also trigger the cells to secrete cytosolic Hsp90 proteins into the extracellular environment (5)(6)(7)(8). Outside the cell, the sole function of extracellular Hsp90␣ (eHsp90␣) is to promote cell motility.…”

Endoplasmic Reticulum Chaperones at the Tumor Cell Surface and in the Extracellular Space

“…Jako stresem indukované proteiny mohou přispí-vat k tumorigenezi a lékové rezistenci, ale současně díky možnosti své specifické inhibice jsou zároveň i nadějnými cíli protinádorové terapie. Naopak nádorové buňky vykazují konstitutivní extracelulární expresi HSP90, obzvlášť v případě nádorů s abnormálně vysokou expresí HIF-1α [66]. Mezi popsané buněčné regulátory sekrece HSP90 patří nádorový supresor p53, HIF-1α a ubikvitin ligáza Hectd1 [65].…”

“…Zvýšené hladiny plazmatického HSP90α byly popsány u pa cientů s karcinomem prsu, plic, pankreatu a jater. Přesto dia gnostický význam detekce HSP90 v krvi zatím není zcela jednoznačný [66].…”