Renal oxygenation suppresses VHL loss-induced senescence that is caused by increased sensitivity to oxidative stress
Scott M Welford1, Mary Jo Dorie, Xiaofeng Li
1Department of Radiation Oncology, Stanford University School of Medicine, 1235 CCSR, 269 Campus Drive, Stanford, CA 93025, USA.
Abstract:
Loss of the VHL tumor suppressor is regarded as an initiating event in the development of clear-cell renal carcinoma. Surprisingly, loss of VHL induces senescence in mouse fibroblasts in vitro, a response that would restrict development of renal carcinoma in vivo. Typical in vitro cell culture levels of oxygen, however, are significantly higher than physiological levels of oxygen, which have been shown to abrogate senescence induced by many stimuli. Therefore, we investigated the oxygen dependence of VHL loss-induced senescence. Using mouse fibroblasts and primary renal epithelial cells in vitro, we found that VHL loss leads to senescence under atmospheric conditions (21% O(2)), partly through increasing p27 levels, but not under physiological oxygenation (2% to 5% O(2)), despite maintaining increased p27 expression. This suggests that VHL inactivation sensitizes cells to oxidative stress. In support of this concept, senescence following VHL loss depends on p53 activity, which decreases under the less stressful conditions of mild hypoxia. We confirmed these observations in vivo by treating kidney-specific VHL knockout animals with the potent oxidizer paraquat and observed a robust induction of cellular senescence. Together, these data demonstrate that in vivo oxygenation promotes tolerance of VHL loss in renal epithelia, which may promote the development of renal carcinoma.
Insights
Loss of VHL tumor suppressor causes senescence in cells at high oxygen but not low oxygen. Physiological oxygen levels in vivo may promote kidney cancer by preventing VHL loss-induced senescence.
Area of Science:
- Oncology
- Cell Biology
- Molecular Biology
Background:
- Loss of the VHL tumor suppressor gene is a key event in clear-cell renal carcinoma development.
- VHL loss typically induces cellular senescence, a state that limits cell proliferation and tumor growth.
- Standard cell culture oxygen levels (21% O2) differ from physiological oxygen levels (2-5% O2), potentially affecting senescence induction.
Purpose of the Study:
- To investigate the role of oxygen levels in VHL loss-induced senescence.
- To determine if physiological oxygenation abrogates senescence in VHL-deficient cells.
- To explore the mechanisms underlying oxygen-dependent senescence in renal carcinoma development.
Main Methods:
- Utilized mouse fibroblasts and primary renal epithelial cells in vitro.
- Compared senescence induction under atmospheric (21% O2) versus physiological (2-5% O2) oxygen conditions.
- Assessed p27 and p53 levels and activity.
- Administered paraquat to kidney-specific VHL knockout mice in vivo.
Main Results:
- VHL loss induced senescence at 21% O2, partly via increased p27.
- Senescence was abrogated at 2-5% O2, despite sustained p27 increase.
- Senescence induction was dependent on p53 activity, which decreased under hypoxia.
- In vivo paraquat treatment of VHL knockout mice robustly induced senescence.
Conclusions:
- In vivo oxygenation promotes tolerance to VHL loss in renal epithelia.
- Physiological oxygen levels may facilitate renal carcinoma development by preventing VHL loss-induced senescence.
- VHL inactivation sensitizes cells to oxidative stress, with p53 and p27 playing key roles in oxygen-dependent senescence.
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