Cycling hypoxia selects for constitutive HIF stabilization
Abstract Tumors experience temporal and spatial fluctuations in oxygenation. Hypoxia inducible transcription factors (HIF-α) respond to low levels of oxygen and induce re-supply oxygen. HIF-α stabilization is typically facultative, induced by hypoxia and reduced by normoxia. In some cancers, HIF-α s...
| Main Authors: | , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2021-03-01
|
| Series: | Scientific Reports |
| Online Access: | https://doi.org/10.1038/s41598-021-85184-8 |
| _version_ | 1818400683021303808 |
|---|---|
| author | Mariyah Pressley Jill A. Gallaher Joel S. Brown Michal R. Tomaszewski Punit Borad Mehdi Damaghi Robert J. Gillies Christopher J. Whelan |
| author_facet | Mariyah Pressley Jill A. Gallaher Joel S. Brown Michal R. Tomaszewski Punit Borad Mehdi Damaghi Robert J. Gillies Christopher J. Whelan |
| author_sort | Mariyah Pressley |
| collection | DOAJ |
| description | Abstract Tumors experience temporal and spatial fluctuations in oxygenation. Hypoxia inducible transcription factors (HIF-α) respond to low levels of oxygen and induce re-supply oxygen. HIF-α stabilization is typically facultative, induced by hypoxia and reduced by normoxia. In some cancers, HIF-α stabilization becomes constitutive under normoxia. We develop a mathematical model that predicts how fluctuating oxygenation affects HIF-α stabilization and impacts net cell proliferation by balancing the base growth rate, the proliferative cost of HIF-α expression, and the mortality from not expressing HIF-α during hypoxia. We compare optimal net cell proliferation rate between facultative and constitutive HIF-α regulation in environments with different oxygen profiles. We find that that facultative HIF-α regulation promotes greater net cell proliferation than constitutive regulation with stochastic or slow periodicity in oxygenation. However, cell fitness is nearly identical for both HIF-α regulation strategies under rapid periodic oxygenation fluctuations. The model thus indicates that cells constitutively expressing HIF-α may be at a selective advantage when the cost of expression is low. In cancer, this condition is known as pseudohypoxia or the “Warburg Effect”. We conclude that rapid and regular cycling of oxygenation levels selects for pseudohypoxia, and that this is consistent with the ecological theory of optimal defense. |
| first_indexed | 2024-12-14T07:40:28Z |
| format | Article |
| id | doaj.art-80fe1800dde0464a95b640975ccb6ff5 |
| institution | Directory Open Access Journal |
| issn | 2045-2322 |
| language | English |
| last_indexed | 2024-12-14T07:40:28Z |
| publishDate | 2021-03-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj.art-80fe1800dde0464a95b640975ccb6ff52022-12-21T23:11:02ZengNature PortfolioScientific Reports2045-23222021-03-0111111410.1038/s41598-021-85184-8Cycling hypoxia selects for constitutive HIF stabilizationMariyah Pressley0Jill A. Gallaher1Joel S. Brown2Michal R. Tomaszewski3Punit Borad4Mehdi Damaghi5Robert J. Gillies6Christopher J. Whelan7Department of Integrated Mathematical Oncology, Moffitt Cancer Center and Research InstituteDepartment of Integrated Mathematical Oncology, Moffitt Cancer Center and Research InstituteDepartment of Integrated Mathematical Oncology, Moffitt Cancer Center and Research InstituteDepartment of Cancer Physiology, Moffitt Cancer Center and Research InstituteDepartment of Cancer Physiology, Moffitt Cancer Center and Research InstituteDepartment of Cancer Physiology, Moffitt Cancer Center and Research InstituteDepartment of Cancer Physiology, Moffitt Cancer Center and Research InstituteDepartment of Cancer Physiology, Moffitt Cancer Center and Research InstituteAbstract Tumors experience temporal and spatial fluctuations in oxygenation. Hypoxia inducible transcription factors (HIF-α) respond to low levels of oxygen and induce re-supply oxygen. HIF-α stabilization is typically facultative, induced by hypoxia and reduced by normoxia. In some cancers, HIF-α stabilization becomes constitutive under normoxia. We develop a mathematical model that predicts how fluctuating oxygenation affects HIF-α stabilization and impacts net cell proliferation by balancing the base growth rate, the proliferative cost of HIF-α expression, and the mortality from not expressing HIF-α during hypoxia. We compare optimal net cell proliferation rate between facultative and constitutive HIF-α regulation in environments with different oxygen profiles. We find that that facultative HIF-α regulation promotes greater net cell proliferation than constitutive regulation with stochastic or slow periodicity in oxygenation. However, cell fitness is nearly identical for both HIF-α regulation strategies under rapid periodic oxygenation fluctuations. The model thus indicates that cells constitutively expressing HIF-α may be at a selective advantage when the cost of expression is low. In cancer, this condition is known as pseudohypoxia or the “Warburg Effect”. We conclude that rapid and regular cycling of oxygenation levels selects for pseudohypoxia, and that this is consistent with the ecological theory of optimal defense.https://doi.org/10.1038/s41598-021-85184-8 |
| spellingShingle | Mariyah Pressley Jill A. Gallaher Joel S. Brown Michal R. Tomaszewski Punit Borad Mehdi Damaghi Robert J. Gillies Christopher J. Whelan Cycling hypoxia selects for constitutive HIF stabilization Scientific Reports |
| title | Cycling hypoxia selects for constitutive HIF stabilization |
| title_full | Cycling hypoxia selects for constitutive HIF stabilization |
| title_fullStr | Cycling hypoxia selects for constitutive HIF stabilization |
| title_full_unstemmed | Cycling hypoxia selects for constitutive HIF stabilization |
| title_short | Cycling hypoxia selects for constitutive HIF stabilization |
| title_sort | cycling hypoxia selects for constitutive hif stabilization |
| url | https://doi.org/10.1038/s41598-021-85184-8 |
| work_keys_str_mv | AT mariyahpressley cyclinghypoxiaselectsforconstitutivehifstabilization AT jillagallaher cyclinghypoxiaselectsforconstitutivehifstabilization AT joelsbrown cyclinghypoxiaselectsforconstitutivehifstabilization AT michalrtomaszewski cyclinghypoxiaselectsforconstitutivehifstabilization AT punitborad cyclinghypoxiaselectsforconstitutivehifstabilization AT mehdidamaghi cyclinghypoxiaselectsforconstitutivehifstabilization AT robertjgillies cyclinghypoxiaselectsforconstitutivehifstabilization AT christopherjwhelan cyclinghypoxiaselectsforconstitutivehifstabilization |