Abstract
Oxygen sensing is crucial for adaptation to variable habitats and physiological conditions. Low oxygen tension, or hypoxia, is a common feature of solid tumors, and hypoxic tumors are often more aggressive and resistant to therapy. Here we show that, in cultured mammalian cells, hypoxia suppressed lysosomal acidification/activation and receptor tyrosine kinase (RTK) degradation. Hypoxia down-regulated mTORc1, reducing its ability to activate transcription factor EB (TFEB), a master regulator of V-ATPase, the lysosomal proton pump. Hypoxia prevented epidermal growth factor receptor (EGFR) degradation in tumor tissues, whereas activation of lysosomes enhanced tumor cell response to anti-EGFR treatment. Our results link oxygen tension and lysosomal activity, provide a molecular explanation of the malignant phenotype associated with hypoxic tumors, and suggest activation of lysosomes may provide therapeutic benefit in RTK-targeted cancer therapy.
Highlights
Hypoxia is a condition in which the body, or a region of the body, is deprived of an adequate oxygen supply
In studying the effect of hypoxia on receptor tyrosine kinase (RTK) activity, we identified a link between hypoxia and receptor signaling
Ligand stimulation with recombinant epidermal growth factor (EGF) resulted in a reduction of EGF receptor (EGFR) levels in cells cultured in normoxia
Summary
Hypoxia is a condition in which the body, or a region of the body, is deprived of an adequate oxygen supply. Lysosomes maintain an acidic environment principally by pumping protons in from the cytosol via the vacuolar H+ -ATPase [4]. The lysosome is a major component of the cellular degradation machinery, digesting damaged and abnormal proteins, as well as directing the proteolysis of cellular enzymes and regulatory proteins that are no longer needed, in order to maintain cellular homeostasis [5,6]. Upon activation by ligand binding, receptors undergo endocytosis and lysosome-mediated receptor degradation to avoid excessive and prolonged signal activation [7,8]
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