Nuclear translocation of haeme oxygenase-1 is associated to prostate cancer

Abstract

The role of oxidative stress in prostate cancer has been increasingly recognised. Acute and chronic inflammations generate reactive oxygen species that result in damage to cellular structures. Haeme oxygenase-1 (HO-1) has cytoprotective effects against oxidative damage. We hypothesise that modulation of HO-1 expression may be involved in the process of prostate carcinogenesis and prostate cancer progression. We thus studied HO-1 expression and localisation in 85 samples of organ-confined primary prostate cancer obtained via radical prostatectomy (Gleason grades 4 -9) and in 39 specimens of benign prostatic hyperplasia (BPH). We assessed HO-1 expression by immunohistochemical staining. No significant difference was observed in the cytoplasmic positive reactivity among tumours (84%), non-neoplastic surrounding parenchyma (89%), or BPH samples (87%) (P ¼ 0.53). Haeme oxygenase-1 immunostaining was detected in the nuclei of prostate cancer cells in 55 of 85 (65%) patients but less often in nonneoplastic surrounding parenchyma (30 of 85, 35%) or in BPH (9 of 39, 23%) (Po0.0001). Immunocytochemical and western blot analysis showed HO-1 only in the cytoplasmic compartment of PC3 and LNCaP prostate cancer cell lines. Treatment with hemin, a well-known specific inducer of HO-1, led to clear nuclear localisation of HO-1 in both cell lines and highly induced HO-1 expression in both cellular compartments. These findings have demonstrated, for the first time, that HO-1 expression and nuclear localisation can define a new subgroup of prostate cancer primary tumours and that the modulation of HO-1 expression and its nuclear translocation could represent new avenues for therapy.

Nuclear Heme Oxygenase-1 (HO-1) Modulates Subcellular Distribution and Activation of Nrf2, Impacting Metabolic and Anti-oxidant Defenses

“…HO-1 has long been identified as proto-oncogenic due to its anti-apoptotic and pro-angiogenic properties (54,55), and there is a positive relationship between high nuclear HO-1 content and severity of prostate cancer (35), Nonetheless, the precise role of HO-1 in cancer biology is far from being completely understood. Cancer cells display altered metabolic circuitry and nutrient uptake to increase proliferation preferentially, leading to glucose-dependent ATP production (Warburg theory).…”

“…Each of these columns was then incubated for 10 min individually with 20 l of 35 S-labeled Nrf2 and fragments (⌬C1-⌬C4). The columns were then washed with copious amounts of phosphate buffer.…”

“…In the present study, mouse embryonic fibroblasts (MEFs) were used, as was a prostate cancer cell line (LnCap) because this cell line and human prostate cancer tissues have enhanced nuclear localization of HO-1 when compared with the normal prostate tissue (35). The present study demonstrates that nuclear HO-1 specifically interacts with Nrf2 in the nucleus to facilitate its sustained stabilization from GSK3␤-mediated proteolytic degradation.…”

“…More recently subcellular localization of HO-1 has been studied in the context of oxidative stress and cancer (30). Although HO-1 is an integral protein of the smooth endoplasmic reticulum (31,32), it can localize to other compartments including caveolae (33), mitochondria (34), and the nucleus (35,36), where it can mediate signaling functions (30).…”

Dynamic thiol/disulphide homeostasis before and after radical prostatectomy in patients with prostate cancer

“…Previous studies demonstrated that ageing, genetic predisposition, androgen hormone levels, dietary factors, inflammation and oxidative stress play crucial role in the initiation and development of PC. Oxidative stress in the development of PC has been under intensive research [4].…”