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Combined Inhibition of Hsp90 and Heme Oxygenase‐1 induces apoptosis and endoplasmic reticulum stress in Melanoma
Author(s) -
Barbagallo Ignazio,
Parenti Rosalba,
Vanella Luca,
Zappalà Agata,
Castruccio Castracani Carlo,
Li Volti Giovanni
Publication year - 2015
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.29.1_supplement.713.8
Subject(s) - heme oxygenase , endoplasmic reticulum , unfolded protein response , viability assay , hsp90 , chemistry , protein kinase b , microbiology and biotechnology , hsp90 inhibitor , heat shock protein , apoptosis , signal transduction , cell growth , cancer research , heme , biology , biochemistry , enzyme , gene
Heat shockproteins are ubiquitous molecular chaperones involved in post‐translational folding, stability, activation and maturation of many proteins that are essential mediators of signal transduction and cell cycle progression. Heat shock protein 90 (Hsp90) has recently emerged as an attractive therapeutic target in cancer treatment because it is a key regulator of various oncogene products and cell‐signalling molecules. Heme oxygenase‐1 (HO‐1; also known as Hsp32) is an inducible enzyme participating in heme degradation and involved in oxidative stress resistance. Recent studies indicate that HO‐1 activation may play a role in tumour development and progression. In the present study we investigated the antitumor effects of combining Hsp90 inhibitor (NMS973) and HO‐1 inhibitor (SnMP) on A375 melanoma cells. Hsp90 inhibitor treatment was able to reduce cell viability and induce endoplasmic reticulum (ER) stress (i.e. Ire1a, ERO1, PDI, BIP and CHOP). Interestingly, no significant effect was observed in reactive oxygen species (ROS) formation. Finally, NMS973 treatment resulted in a significant HO‐1 overexpression. Interestingly, the combination of NMS973 and SnMP produced an increase of ROS and reduced cell viability respect NMS973 treatment alone. The inhibitors combination exhibited higher ER stress, apoptosis as evidenced by BFAR mRNA expression and lower phosphorylation of Akt when compared to NMS973 alone. In conclusion, these data suggest that combined inhibition of Hsp90 and HO‐1 is a promising strategy for melanoma treatment.