Blockade of extracellular heat shock protein 90α by 1G6-D7 attenuates pulmonary fibrosis through inhibiting ERK signaling

Abstract

Pulmonary fibrosis is characterized by lung fibroblast activation and ECM deposition and has a poor prognosis. Heat shock protein 90 (Hsp90) participates in organ fibrosis, and extracellular Hsp90α (eHsp90α) promotes fibroblast activation and migration. This study aimed to investigate whether a selective anti-Hsp90α monoclonal antibody, 1G6-D7, could attenuate lung fibrosis and whether 1G6-D7 presents a protective effect by inactivating the profibrotic pathway. Our results showed that eHsp90α was increased in mice with BLM-induced pulmonary fibrosis and that 1G6-D7 attenuated inflammation and collagen deposition in the lung. TGF-β1 induced eHsp90α secretion, concomitantly promoting HFL-1 activation and ECM synthesis. 1G6-D7-mediated inhibition of eHsp90α significantly blocked these effects, meanwhile inhibiting downstream profibrotic pathways such as ERK, Akt, and P38. Human recombinant (hr)Hsp90α mimicked the effects of TGF-β1, by activating profibrotic pathways and by upregulating LRP-1. Moreover, ERK inhibition effectively blocked the effect of (hr)Hsp90α. In conclusion, 1G6-D7 significantly protects against BLM-induced pulmonary fibrosis by ameliorating fibroblast activation and ECM production, which may be through blocking ERK signaling. Our results suggest a safer molecular therapy, 1G6-D7, in pulmonary fibrosis.

The role of collagen in cancer: from bench to bedside

“…Interfering collagen biosynthesis enzymes Collagen genes MiR-129-5p, MiR-29b, MiR-384 [275][276][277] Prolyl 4-hydroxylase Budesonide, catechol, N-oxalylglycine, coumalic acid, ethyl dihydroxybenzoic acid [278][279][280] Heat shock protein 90 1G6-D7, dipalmitoyl-radicicol, 17-DMAG, ganetespib [281][282][283][284] Heat shock protein 47 MiR-29, 1,3-dimethylol-5-FU, AK778, pirfenidone, terutroban [285,286] Matrix metalloproteinases Gallium complex GS2, isoflavonoids, bisphosphonates [287,288] Lysyl oxidases Beta-aminopropionitrile [289] Disturbing cancer cell signaling pathways Snail transcription factors Toosendanin, ponicidin, ferulic acid [290] Hypoxia-inducible factor Tamoxifen, 28-O-propynoylbetulin [291,292] STAT3 signaling pathway VS-4718, stattic, ruxolitinib, S3I-201 [293,294] TGF-β signaling pathway LY2157299 monohydrate, trabedersen, fresolimumab, galunisertib [295,296] NF-κB signaling pathway Honokiol, aspirin, ormeloxifene [297][298][299] AKT signaling pathway Quetiapine, pirfenidone [300] Notch signaling pathway Rovalpituzumab tesirine, taladegib, crenigacestat, MiR-148a [301] Hedgehog signaling pathway Itraconazole, sonidegib, vismodegib [302] RAS signaling pathway Perindopril, losartan [100,303] Tyrosine kinase receptor Bevacizumab, imatinib, ponatinib, dasatinib [304,305] Discoidin domain receptor WRG-28, 7rh, AZD0156 [306][307][308] G protein family receptor AT13148, KD025, Azaindole 1, chelerythrine…”

HSP90 Inhibition and Modulation of the Proteome: Therapeutical Implications for Idiopathic Pulmonary Fibrosis (IPF)

“…Additionally, in a preliminary study, we observed increased HSP90 immunoreactivity in pneumocytes, airway epithelium, and fibroblast foci in areas of active fibrosis in rabbits with chemical-induced PF (Figure 3). HSP90α is able to promote the phosphorylation of Protein kinase B (AKT) in Thr308, P38, and extracellular signal-regulated kinase (ERK) signaling pathways, which are known downstream non-Smad-pathways of TGFβ1 signaling and participate in the development of pulmonary fibrosis [66]. Indeed, HSP90 has been shown to regulate ERK directly via dissociation of the ERK-HSP90-CDC37 complex [70] and indirectly by negatively inhibiting Raf metabolism and its downstream cascade [71].…”

“…HSP90 has also been found increased in animal models of pulmonary fibrosis. In the bleomycin-induced mouse model, BALF and serum displayed high levels of HSP90α and this increase was related to fibrosis [66]. Activated HSP90, phospho-HSP90, was elevated in lung tissue of mice with hydrochloric acid (HCl)-induced pulmonary fibrosis at 10 and 30 days after acid instillation, compared to controls [68].…”

“…The effect on the kinome, after HSP90 inhibitors application showed downregulation in 70% kinases of Hs68 cells (144 quantified kinases), including MAPK and TGF-β signaling pathways [87]. 1G6-D7, another HSP90α inhibitor, attenuated the severity of the fibrotic process in a murine model of Bleomycin-induced pulmonary fibrosis by lowering the circulating levels of HSP90α [66]. NVP-AUY922, a highly potent HSP90 inhibitor with improved bioavailability and aqueous solubility compared to first generation HSP90 inhibitors [88], successfully inhibited both HSP90α and HSP90β with similar median inhibition concentration (IC50) values [89].…”

Heat shock protein-90 toward theranostics: a breath of fresh air in idiopathic pulmonary fibrosis

“…Although HSP90 extracellular activities are not fully understood at the moment, the approach taken by BELLAYE et al [19] might have several advantages in case of long-term treatments with HSP90 inhibitors, which will be most likely the case in chronic conditions such as IPF. Moreover, these findings have recently been confirmed in mice with 1G6-D7, a cell impermeable antibody raised against HSP90α, which hampered bleomycin-induced pulmonary fibrosis [27]. However, the authors injected 1G6-D7 starting the following day post-bleomycin thus before lung fibrosis has occurred.…”