PTEN deletion and heme oxygenase‐1 overexpression cooperate in prostate cancer progression and are associated with adverse clinical outcome

Abstract

Overexpression of the pro-survival protein heme oxygenase-1 (HO-1) and loss of the pro-apoptotic tumour suppressor PTEN are common events in prostate cancer (PCA). We assessed the occurrence of both HO-1 expression and PTEN deletion in two cohorts of men with localized and castration-resistant prostate cancer (CRPC). The phenotypic cooperation of these markers was examined in preclinical and clinical models. Overall, there was a statistically significant difference in HO-1 epithelial expression between benign, high-grade prostatic intraepithelial neoplasia (HGPIN), localized PCA, and CRPC (p < 0.0001). The highest epithelial HO-1 expression was noted in CRPC (2.00 ± 0.89), followed by benign prostate tissue (1.49 ± 1.03) (p = 0.0003), localized PCA (1.20 ± 0.95), and HGPIN (1.07 ± 0.87) (p < 0.0001). However, the difference between HGPIN and PCA was not statistically significant (p = 0.21). PTEN deletions were observed in 35/55 (63.6%) versus 68/183 (37.1%) cases of CRPC and localized PCA, respectively. Although neither HO-1 overexpression nor PTEN deletions alone in localized PCA showed a statistically significant association with PSA relapse, the combined status of both markers correlated with disease progression (log-rank test, p = 0.01). In a preclinical model, inhibition of HO-1 by shRNA in PTEN-deficient PC3M cell line and their matched cells where PTEN is restored strongly reduced cell growth and invasion in vitro and inhibited tumour growth and lung metastasis formation in mice compared to cells where only HO-1 is inhibited or PTEN is restored. In summary, we provide clinical and experimental evidence for cooperation between epithelial HO-1 expression and PTEN deletions in relation to the PCA patient's outcome. These findings could potentially lead to the discovery of novel therapeutic modalities for advanced PCA.

Hypoxia-Induced Gene Expression in Chemoradioresistant Cervical Cancer Revealed by Dynamic Contrast-Enhanced MRI

“…However, several of them or their encoded proteins, including STC2, PFKFB4, RHOC, S100A2, HMOX1, and ISG15, have been associated with poor prognosis in other cancer types (39)(40)(41)(42)(43)(44). Moreover, upregulation of ALDOA, GAPDH, and PFKFB4 suggest a high glycolytic activity, as mentioned above, which has been associated with aggressiveness (28).…”

A Prospective Investigation of PTEN Loss and ERG Expression in Lethal Prostate Cancer

“…Most previous studies investigating the prognostic role of PTEN have used biochemical recurrence as the primary outcome, with the majority finding that loss is associated with an increased risk of biochemical recurrence (7,9,11,37-39), but results are not entirely consistent (8,31,40). A limitation of using biochemical recurrence as an outcome is that only a small subset of cases who experience biochemical recurrence will die of prostate cancer (41).…”

Bortezomib induces heme oxygenase-1 expression in multiple myeloma

“…HO-1 overexpression has also been described in relapse or recurrent malignancies. 27 To explore the molecular basis of acquired resistance to bortezomib and lenalidomide, MM cell lines RPMI8226 and MM1S cells were exposed in vitro over a period of 3 mo to step-wise increasing concentrations of bortezomib (1 nM to 50 nM) and lenalidomide (500 nM to 20 μM). RPMI8226 and MM1S cells grown in the presence of 20 and 50 nM bortezomib (Bz20 and Bz50), 10 and 20 μM lenalidomide (Len10 and Len20) were used for characterization.…”