Abstract
Response to hypoxia is a highly regulated process, but little is known about single-cell responses to hypoxic conditions. Using fluorescent reporters of hypoxia response factor-1α (HIF-1α) activity in various cancer cell lines and patient-derived cancer cells, we show that hypoxic responses in individual cancer cells can be highly dynamic and variable. These responses fall into three classes, including oscillatory activity. We identify a molecular mechanism that can account for all three response classes, implicating reactive-oxygen-species-dependent chaperone-mediated autophagy of HIF-1α in a subset of cells. Furthermore, we show that oscillatory response is modulated by the abundance of extracellular lactate in a quorum-sensing-like mechanism. We show that oscillatory HIF-1α activity rescues hypoxia-mediated inhibition of cell division and causes broad suppression of genes downregulated in cancers and activation of genes upregulated in many cancers, suggesting a mechanism for aggressive growth in a subset of hypoxic tumor cells.
Original language | English (US) |
---|---|
Pages (from-to) | 1048-1064.e7 |
Journal | Cell Systems |
Volume | 13 |
Issue number | 12 |
DOIs | |
State | Published - Dec 21 2022 |
Keywords
- HIF
- ROS
- Warburg and reverse Warburg effect
- cancer microenvironment
- chaperone-mediated autophagy
- hypoxia
- hypoxic oscillations
- lactate
- quorum sensing
- reactive oxygen species
ASJC Scopus subject areas
- Pathology and Forensic Medicine
- Cell Biology
- Histology