Lactate-dependent chaperone-mediated autophagy induces oscillatory HIF-1α activity promoting proliferation of hypoxic cells

Kshitiz; Junaid Afzal; Yasir Suhail; Hao Chang; Maimon E Hubbi; Archer Hamidzadeh; Ruchi Goyal; Yamin Liu; Peng Sun; Stefania Nicoli; Chi V Dang; Andre Levchenko

doi:10.1016/j.cels.2022.11.003

Lactate-dependent chaperone-mediated autophagy induces oscillatory HIF-1α activity promoting proliferation of hypoxic cells

Cell Syst. 2022 Dec 21;13(12):1048-1064.e7. doi: 10.1016/j.cels.2022.11.003. Epub 2022 Dec 2.

Authors

Kshitiz¹, Junaid Afzal², Yasir Suhail³, Hao Chang⁴, Maimon E Hubbi⁵, Archer Hamidzadeh⁴, Ruchi Goyal⁶, Yamin Liu⁷, Peng Sun², Stefania Nicoli⁸, Chi V Dang⁹, Andre Levchenko¹⁰

Affiliations

¹ Department of Biomedical Engineering, University of Connecticut Health Center, Farmington, CT 06032, USA; Department of Oncology, The Johns Hopkins Medical Institutions, Baltimore, MD 21287, USA. Electronic address: kshitiz@uchc.edu.
² Department of Oncology, The Johns Hopkins Medical Institutions, Baltimore, MD 21287, USA.
³ Department of Biomedical Engineering, University of Connecticut Health Center, Farmington, CT 06032, USA; Department of Oncology, The Johns Hopkins Medical Institutions, Baltimore, MD 21287, USA.
⁴ Department of Biomedical Engineering, Yale University, New Haven, CT 06520, USA; Yale Systems Biology Institute, Yale University, Orange, CT 06477, USA.
⁵ Department of Oncology, The Johns Hopkins Medical Institutions, Baltimore, MD 21287, USA; Department of Genetics, Yale University, New Haven, CT 06520, USA.
⁶ Department of Biomedical Engineering, University of Connecticut Health Center, Farmington, CT 06032, USA; Yale Systems Biology Institute, Yale University, Orange, CT 06477, USA.
⁷ Department of Biomedical Engineering, University of Connecticut Health Center, Farmington, CT 06032, USA.
⁸ Department of Genetics, Yale University, New Haven, CT 06520, USA.
⁹ Department of Oncology, The Johns Hopkins Medical Institutions, Baltimore, MD 21287, USA; Ludwig Institute for Cancer Research, New York, NY 10016, USA; The Wistar Institute, Philadelphia, PA 19104, USA. Electronic address: cdang@lcr.org.
¹⁰ Department of Biomedical Engineering, Yale University, New Haven, CT 06520, USA; Yale Systems Biology Institute, Yale University, Orange, CT 06477, USA. Electronic address: andre.levchenko@yale.edu.

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.

Keywords: HIF; ROS; Warburg and reverse Warburg effect; cancer microenvironment; chaperone-mediated autophagy; hypoxia; hypoxic oscillations; lactate; quorum sensing; reactive oxygen species.

Publication types

Research Support, N.I.H., Extramural

MeSH terms

Cell Line, Tumor
Cell Proliferation
Chaperone-Mediated Autophagy*
Humans
Hypoxia / metabolism
Lactic Acid* / metabolism

Substances

Lactic Acid

Abstract

Publication types

MeSH terms

Substances

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