A novel experimental heme oxygenase-1-targeted therapy for hormone-refractory prostate cancer.
Heme oxygenase-1 (HO-1), a member of the heat shock protein family, plays a key role as a sensor and regulator of oxidative stress. Herein, we identify HO-1 as a biomarker and potential therapeutic target for advanced prostate cancer (PCA). Immunohistochemical analysis of prostate tissue using a progression tissue microarray from patients with localized PCA and across several stages of disease progression revealed a significant elevation of HO-1 expression in cancer epithelial cells, but not in surrounding stromal cells, from hormone-refractory PCA (HRPCA) compared with hormone-responsive PCA and benign tissue. Silencing the ho-1 gene in HRPCA cells decreased the HO-1 activity, oxidative stress, and activation of the mitogen-activated protein kinase-extracellular signal-regulated kinase/p38 kinase. This coincided with reduced cell proliferation, cell survival, and cell invasion in vitro, as well as inhibition of prostate tumor growth and lymph node and lung metastases in vivo. The effect of ho-1 silencing on these oncogenic features was mimicked by exposure of cells to a novel selective small-molecule HO-1 inhibitor referred to as OB-24. OB-24 selectively inhibited HO-1 activity in PCA cells, which correlated with a reduction of protein carbonylation and reactive oxygen species formation. Moreover, OB-24 significantly inhibited cell proliferation in vitro and tumor growth and lymph node/lung metastases in vivo. A potent synergistic activity was observed when OB-24 was combined with Taxol. Together, these results establish HO-1 as a potential therapeutic target for advanced PCA.
Alaoui-Jamali
Moulay A
MA
Department of Medicine, Lady Davis Institute of Medical Research, Segal Cancer Centre, McGill University, Montreal, Quebec, Canada. moulay.alaoui-jamali@mcgill.ca
Bismar
Tarek A
TA
Gupta
Ajay
A
Szarek
Walter A
WA
Su
Jie
J
Song
Wei
W
Xu
Yingjie
Y
Xu
Bin
B
Liu
Guoan
G
Vlahakis
Jason Z
JZ
Roman
Gheorghe
G
Jiao
Jinsong
J
Schipper
Hyman M
HM
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D002448:Cell Adhesion / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D018450:Disease Progression; D015971:Gene Expression Regulation, Enzymologic; D015316:Genetic Therapy; D051547:Heme Oxygenase-1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007124:Immunoenzyme Techniques; D008175:Lung Neoplasms / Q000201:enzymology / Q000517:prevention & control* / Q000556:secondary; D008207:Lymphatic Metastasis; D008297:Male; D051379:Mice; D016513:Mice, SCID; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D009361:Neoplasm Invasiveness; D009376:Neoplasms, Hormone-Dependent / Q000201:enzymology / Q000517:prevention & control* / Q000556:secondary; D018384:Oxidative Stress; D011470:Prostatic Hyperplasia / Q000201:enzymology / Q000473:pathology / Q000517:prevention & control*; D011471:Prostatic Neoplasms / Q000201:enzymology / Q000473:pathology / Q000517:prevention & control*; D034741:RNA, Small Interfering / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction; D046888:Tissue Array Analysis; D014407:Tumor Cells, Cultured; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; C496541:HMOX1 protein, human; D051547:Heme Oxygenase-1; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D048051:p38 Mitogen-Activated Protein Kinases