Hypoxia-selective macroautophagy and cell survival signaled by autocrine PDGFR activity.
The selective regulation of macroautophagy remains poorly defined. Here we report that PDGFR signaling is an essential selective promoter of hypoxia-induced macroautophagy. Hypoxia-induced macroautophagy in tumor cells is also HIF1alpha-dependent, with HIF1alpha integrating signals from PDGFRs and oxygen tension. Inhibition of PDGFR signaling reduces HIF1alpha half-life, despite buffering of steady-state protein levels by a compensatory increase in HIF1alpha mRNA. This markedly changes HIF1alpha protein pool dynamics, and consequently reduces the HIF1alpha transcriptome. As autocrine growth factor signaling is a hallmark of many cancers, cell-autonomous enhancement of HIF1alpha-mediated macroautophagy may represent a mechanism for augmenting tumor cell survival under hypoxic conditions.
Wilkinson
Simon
S
Tumour Cell Death Laboratory, Beatson Institute for Cancer Research, Glasgow, United Kingdom.
O'Prey
Jim
J
Fricker
Michael
M
Ryan
Kevin M
KM
D000818:Animals; D051784:Aryl Hydrocarbon Receptor Nuclear Translocator / Q000378:metabolism; D019898:Autocrine Communication; D001343:Autophagy / Q000502:physiology*; D002460:Cell Line; D045744:Cell Line, Tumor; D002470:Cell Survival; D003600:Cytosol / Q000378:metabolism; D004331:Drosophila melanogaster / Q000378:metabolism; D045325:HCT116 Cells; D006801:Humans; D000860:Hypoxia; D017479:Receptors, Platelet-Derived Growth Factor / Q000378:metabolism*; D015398:Signal Transduction
D051784:Aryl Hydrocarbon Receptor Nuclear Translocator; D017479:Receptors, Platelet-Derived Growth Factor