In vivo hyperoxia induces hypoxia-inducible factor-1α overexpression in LNCaP tumors without affecting the tumor growth rate.
Hypoxia is a recognized cause for solid tumors malignancy and resistance, probably via hypoxia-induced overexpression of the hypoxia-inducible factor (HIF)-1α, major modulator of the cell response to oxygen deprivation. Although hyperoxia, the opposite condition, may represent a key issue to assess this paradigm, its effect on tumor growth and HIF-1α expression remains unclear. To test whether hyperoxia and hypoxia have divergent effects, and to better focus into the role of HIF-1α in vivo, athymic mice xenografted with LNCaP cells were exposed for 28 days to atmospheres containing 10, 21 or 30% O2. Whereas the xenografts grew twice faster in hypoxia, their growth rates in hyperoxia and normoxia were similar. To analyze the involved molecular mechanisms, we performed various assays in xenograft tissues. Faster xenografts growth in hypoxia was associated with higher phosphorylation of protein kinase B (Akt) and higher expression of Ki67, both related with pro-survival and cell proliferation pathways. By contrast, the expression level of HIF-1α was similar in normoxia and hypoxia, but paradoxically twice higher in hyperoxia. The protein level of the nuclear factor (erythroid-derived 2)-like 2 (Nrf2) was also higher in hyperoxia, suggesting marked cell response to redox imbalance. Whereas both the vascular-endothelial growth factor (VEGF) and its receptor VEGF-R2 were overexpressed in hyperoxia, the tissue hemoglobin content was not increased, despite a slight reduction in vascularization. As a whole, this data indicates that the xenografts growth rate was independent of HIF-1α expression level, suggesting that in an in vivo setting alternative more effective proliferative paths associated with the cell response to the redox imbalance may override the paths linked to HIF-1α signaling.
Department of Health Science, San Paolo Hospital, University of Milan, Italy.
Laura
L
Terraneo
Department of Health Science, San Paolo Hospital, University of Milan, Italy.
Eleonora
E
Virgili
Department of Health Science, San Paolo Hospital, University of Milan, Italy.
Anna
A
Caretti
Department of Health Science, San Paolo Hospital, University of Milan, Italy.
Paola
P
Bianciardi
Department of Health Science, San Paolo Hospital, University of Milan, Italy. Electronic address: michele.samaja@unimi.it.
Michele
M
Samaja
D000818:Animals; D015687:Cell Hypoxia / Q000502:physiology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000502:physiology; D064593:Heterografts; D000860:Hypoxia / Q000378:metabolism* / Q000473:pathology*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000096:biosynthesis*; D008297:Male; D051379:Mice; D009389:Neovascularization, Pathologic; D010766:Phosphorylation; D017430:Prostate-Specific Antigen / Q000097:blood; D011471:Prostatic Neoplasms / Q000378:metabolism* / Q000473:pathology*; D015398:Signal Transduction
D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D017430:Prostate-Specific Antigen
Angiogenesis; Hypoxia-inducible factor; In vivo hyperoxia; In vivo hypoxia; LNCaP tumor