Cigarette smoke induces nuclear translocation of heme oxygenase 1 (HO-1) in prostate cancer cells: Nuclear HO-1 promotes vascular endothelial growth factor secretion

Abstract

Prostate cancer is the second leading cause of male-cancer related death in the United States. Despite a number of evidence-based studies which strongly suggest an association between cigarette smoking and prostate cancer, the underlying biological mechanism is largely unknown. Heme oxygenase 1 (HO-1) has been implicated in maintaining cellular homeostasis, but also in tumor angiogenesis. Nuclear HO-1 protein expression has been observed in various types of tumors including prostate cancer. These studies, however, were reported as clinical and pathological observations, and failed to investigate nuclear HO-1 at the molecular level in cancer. The present study explores the relationship between cigarette smoke and nuclear HO-1-modulated promotion of vascular endothelial growth factor (VEGF) secretion. We have demonstrated that cigarette smoke medium (SM)-induced HO-1 mRNA expression and upregulated HO-1 protein levels in the prostate cancer cell lines DU145 and PC3. We also observed that SM significantly induced nuclear expression of HO-1, and enhanced secretion of VEGF in cells. Nuclear-directed expression of HO-1 activated the transcriptional activity of VEGF and promoted VEGF secretion in prostate cancer cells. This study provides new insights into the molecular mechanism by which cigarette smoke-induced nuclear translocation of HO-1 promotes VEGF secretion in prostate cancer cells. Nuclear HO-1 may, therefore, constitute an attractive therapeutic target to inhibit angiogenesis and the progression of prostate cancer.

HO-1/CO system in tumor growth, angiogenesis and metabolism — Targeting HO-1 as an anti-tumor therapy

“…Increased angiogenesis in relation to enhanced HO-1 expression has been noted for several types of tumors, including Kaposi sarcoma [48], prostate cancer [49], melanoma [50], pancreatic cancer [51], glioma [52] and LL/2 mouse lung cancer [53]. HO-1/CO is involved in the angiogenic pathways driven by VEGF and stromal cell-derived factor-1 (SDF-1), the two major angiogenic mediators (for review see: [33, 54,55]).…”

Association of Cigarette Smoking and Smoking Cessation with Biochemical Recurrence of Prostate Cancer in Patients Treated with Radical Prostatectomy

“…In a recent in vitro study, cigarette smoke medium induced HO1 mRNA expression and upregulated HO1 protein levels in the PCa cell lines DU145 and PC3 [14]. Expression of HO1 activated the transcriptional activity of vascular endothelial growth factor (VEGF) and promoted VEGF secretion in PCa cells [14]. As VEGF expression is associated with PCa prognosis [15], these results warrant further confirmation in animal models.…”

“…One potential mechanism linking smoking and PCa recurrence is the induction of heme oxygenase 1 (HO1) expression in PCa cells. In a recent in vitro study, cigarette smoke medium induced HO1 mRNA expression and upregulated HO1 protein levels in the PCa cell lines DU145 and PC3 [14]. Expression of HO1 activated the transcriptional activity of vascular endothelial growth factor (VEGF) and promoted VEGF secretion in PCa cells [14].…”

Was wissen Patienten mit einem Prostatakarzinom über das Rauchen?

“…Ein dritter Erklärungsansatz kann in der Zunahme der genetischen und epigenetischen Instabilität von PCA-Zellen bei Rauchern liegen, wobei die daraus resultierenden molekularen Aberrationen durchaus ein verändertes biologisches und klinisches Verhalten des PCA bewirken können (beispielsweise durch ein aggressiveres Wachstum und höhere Motilität der Tumorzellen). In-vitroModellversuche konnten nachweisen, dass bei Rauchern eine höhere Expression von Hämooxygenase-1-(HO-1-)-mRNA vorliegt, was dann wiederum zu einer gesteigerten Tumorangiogenese führte [20,21]. Ein weiterer Weg zur hö-heren Tumorprogression bedingt durch das Zigarettenrauchen wurde durch die stärkere Methylierung von Cytidin-pGuanosin-Inseln beschrieben [22,23].…”