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The unfolded protein response protects human tumor cells during hypoxia through regulation of the autophagy genes MAP1LC3B and ATG5
Kasper M.A. Rouschop, … , Marianne Koritzinsky, Bradly G. Wouters
Kasper M.A. Rouschop, … , Marianne Koritzinsky, Bradly G. Wouters
Published December 14, 2009
Citation Information: J Clin Invest. 2010;120(1):127-141. https://doi.org/10.1172/JCI40027.
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Research Article Oncology

The unfolded protein response protects human tumor cells during hypoxia through regulation of the autophagy genes MAP1LC3B and ATG5

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Abstract

Tumor hypoxia is a common microenvironmental factor that adversely influences tumor phenotype and treatment response. Cellular adaptation to hypoxia occurs through multiple mechanisms, including activation of the unfolded protein response (UPR). Recent reports have indicated that hypoxia activates a lysosomal degradation pathway known as autophagy, and here we show that the UPR enhances the capacity of hypoxic tumor cells to carry out autophagy, and that this promotes their survival. In several human cancer cell lines, hypoxia increased transcription of the essential autophagy genes microtubule-associated protein 1 light chain 3β (MAP1LC3B) and autophagy-related gene 5 (ATG5) through the transcription factors ATF4 and CHOP, respectively, which are regulated by PKR-like ER kinase (PERK, also known as EIF2AK3). MAP1LC3B and ATG5 are not required for initiation of autophagy but mediate phagophore expansion and autophagosome formation. We observed that transcriptional induction of MAP1LC3B replenished MAP1LC3B protein that was turned over during extensive hypoxia-induced autophagy. Correspondingly, cells deficient in PERK signaling failed to transcriptionally induce MAP1LC3B and became rapidly depleted of MAP1LC3B protein during hypoxia. Consistent with these data, autophagy and MAP1LC3B induction occurred preferentially in hypoxic regions of human tumor xenografts. Furthermore, pharmacological inhibition of autophagy sensitized human tumor cells to hypoxia, reduced the fraction of viable hypoxic tumor cells, and sensitized xenografted human tumors to irradiation. Our data therefore demonstrate that the UPR is an important mediator of the hypoxic tumor microenvironment and that it contributes to resistance to treatment through its ability to facilitate autophagy.

Authors

Kasper M.A. Rouschop, Twan van den Beucken, Ludwig Dubois, Hanneke Niessen, Johan Bussink, Kim Savelkouls, Tom Keulers, Hilda Mujcic, Willy Landuyt, Jan Willem Voncken, Philippe Lambin, Albert J. van der Kogel, Marianne Koritzinsky, Bradly G. Wouters

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Figure 9

Model for recycling and regeneration of MAP1LC3B during hypoxia.

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Model for recycling and regeneration of MAP1LC3B during hypoxia.
During ...
During the process of autophagy, the extending membrane (phagophore) requires coating with MAP1LC3B to form an autophagosome. The ATG5-ATG12-ATG16 complex redistributes and recruits MAP1LC3B to the membrane. Before degradation of the autolysosomal content, the ATG5-ATG12-ATG16 complex and the MAP1LC3B at the outer membrane is released to be recycled and the portion of MAP1LC3B inside the autolysosome is degraded. Hypoxia activates autophagy through BNIP3/BNIP3L signaling or AMPK (initiation). Activation of UPR/PERK signaling increases the capacity to maintain autophagy as it replenishes the overturned MAP1LC3B, but this activation also increases ATG5 expression to form ATG5-ATG12-ATG16 complexes.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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