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Cited by 188Autophagy in Disease and TherapyCancer, Hypoxia, and MetabolismUbiquitin and proteasome pathways

The DOI matches its Crossref record; 213 of the 216 references it cites were found in a registry or an index.

Hypoxia and Selective Autophagy in Cancer Development and Therapy

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Daskalaki, Ioanna, Gkikas, Ilias, Tavernarakis, Nektarios·2018·Frontiers in Cell and Developmental Biology
DOI 10.3389/fcell.2018.00104PMC PMC6139351
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Abstract

Low oxygen availability, a condition known as hypoxia, is a common feature of various pathologies including stroke, ischemic heart disease, and cancer. Hypoxia adaptation requires coordination of intricate pathways and mechanisms such as hypoxia-inducible factors (HIFs), the unfolded protein response (UPR), mTOR, and autophagy. Recently, great effort has been invested toward elucidating the interplay between hypoxia-induced autophagy and cancer cell metabolism. Although novel types of selective autophagy have been identified, including mitophagy, pexophagy, lipophagy, ERphagy and nucleophagy among others, their potential interface with hypoxia response mechanisms remains poorly understood. Autophagy activation facilitates the removal of damaged cellular compartments and recycles components, thus promoting cell survival. Importantly, tumor cells rely on autophagy to support self-proliferation and metastasis; characteristics related to poor disease prognosis. Therefore, a deeper understanding of the molecular crosstalk between hypoxia response mechanisms and autophagy could provide important insights with relevance to cancer and hypoxia-related pathologies. Here, we survey recent findings implicating selective autophagy in hypoxic responses, and discuss emerging links between these pathways and cancer pathophysiology.

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Figure 1 HIF-1, UPR, and mTOR coordinate hypoxia-induced autophagy. To cope with low oxygen levels, cells evoke different oxygen-sensing pathways such as HIF-1, UPR, and mTOR which are tightly coordinated and regularly converge on autophagy. When oxygen is abundant HIF-1 is hydroxylated by prolyls hydroxylases (PHDs) and ubiquitinated by von Hippel Lindau (pVHL) protein. These combined actions result in HIF-1 degradation from the proteasome. In response to hypoxia, HIF-1 is stabilized and translocates to the nucleus to initiate the transcription of multiple genes involved in autophagy, glucose metabolism and mitochondria respiration, among others. Importantly, HIF-1 regulates essential genes for the assembly and function of the autophagy machinery. Particularly, expression of NIX, Beclin 1, ATG5, BNIP3, PIK3C3, ATG7, and ATG9A has been documented to be HIF-1-dependent. Notably, the expression of key glycolytic enzymes that are direct targets of HIF-1 has also been associated with the autophagy process. Specifically, expression of GLUT1, HK2, PGK1, ENO1, PDK1, and PFKFB3 has been reported to be HIF-1-dependent. Surprisingly, in response to oxygen and/or glucose deprivation, expression of HIF-1 targets is linked with the autophagy process. In this respect, hypoxia-induced AMPK negatively regulates mTOR signaling which in turn drives autophagy initiation through ULK1 phosphorylation (bulk and selective autophagy i.e., ERphagy, mitophagy, pexophagy shown here). Similarly, PTEN can inhibit mTOR upon hypoxia and subsequently control autophagy. To this direction, during periods of oxygen limitation cells respond by activating UPR which requires the action of three signaling proteins comprising PERK, IRE1, and ATF6. In the course of PERK-mediated response, eIF2α is phosphorylated to prevent mRNA translation. Moreover, upon hypoxia PERK controls regulation of ATF4 and CHOP which in turn orchestrate the activity of autophagy-related proteins. The contribution of IRE1/XBP1 and ATF6 arms of UPR in autophagy upon hypoxia has just emerged. Although the exact associations with and within UPR, mTOR, HIF-1, and autophagy remain elusive upon hypoxia, identification of XBP1, ATG4, and REDD-1 among others, further supports this notion and highlights the complexity of the system.
Figure 1 HIF-1, UPR, and mTOR coordinate hypoxia-induced autophagy. To cope with low oxygen levels, cells evoke different oxygen-sensing pathways such as HIF-1, UPR, and mTOR which are tightly coordinated and regularly converge on autophagy. When oxygen is abundant HIF-1 is hydroxylated by prolyls hydroxylases (PHDs) and ubiquitinated by von Hippel Lindau (pVHL) protein. These combined actions result in HIF-1 degradation from the proteasome. In response to hypoxia, HIF-1 is stabilized and translocates to the nucleus to initiate the transcription of multiple genes involved in autophagy, glucose metabolism and mitochondria respiration, among others. Importantly, HIF-1 regulates essential genes for the assembly and function of the autophagy machinery. Particularly, expression of NIX, Beclin 1, ATG5, BNIP3, PIK3C3, ATG7, and ATG9A has been documented to be HIF-1-dependent. Notably, the expression of key glycolytic enzymes that are direct targets of HIF-1 has also been associated with the autophagy process. Specifically, expression of GLUT1, HK2, PGK1, ENO1, PDK1, and PFKFB3 has been reported to be HIF-1-dependent. Surprisingly, in response to oxygen and/or glucose deprivation, expression of HIF-1 targets is linked with the autophagy process. In this respect, hypoxia-induced AMPK negatively regulates mTOR signaling which in turn drives autophagy initiation through ULK1 phosphorylation (bulk and selective autophagy i.e., ERphagy, mitophagy, pexophagy shown here). Similarly, PTEN can inhibit mTOR upon hypoxia and subsequently control autophagy. To this direction, during periods of oxygen limitation cells respond by activating UPR which requires the action of three signaling proteins comprising PERK, IRE1, and ATF6. In the course of PERK-mediated response, eIF2α is phosphorylated to prevent mRNA translation. Moreover, upon hypoxia PERK controls regulation of ATF4 and CHOP which in turn orchestrate the activity of autophagy-related proteins. The contribution of IRE1/XBP1 and ATF6 arms of UPR in autophagy upon hypoxia has just emerged. Although the exact associations with and within UPR, mTOR, HIF-1, and autophagy remain elusive upon hypoxia, identification of XBP1, ATG4, and REDD-1 among others, further supports this notion and highlights the complexity of the system.CC BY · PubMed Central
Figure 2 Regulation of FUNDC1-mediated mitophagy in normoxia versus hypoxia. FUNDC1 is inactivated upon normoxia by two phosphorylation events at Tyr18 and Ser13. Phosphorylation at these sites is accomplished by the Src and CK2 kinases, respectively and renders the LIR motif of FUNDC1 inaccessible to LC3. Also, OPA1 binds FUNDC1 in the intermembrane space, promoting mitochondrial fusion. miR-137, which targets the 3′ UTR of FUNDC1 mRNA is upregulated upon normoxia, thus blocking protein synthesis. In parallel, BCL-xL binds PGAM5 and renders it dormant and additionally, the E3 ubiquitin ligase physically interacts with FUNDC1, ubiquitinates it and triggers its proteasomal degradation. This effect is also evident just at the onset of hypoxia. Following, Src kinase is inactivated through phosphorylation on its Tyr416 residue. Src inactivation further blocks Tyr18 phosphorylation on FUNDC1. Moreover, OPA1 dissociates from FUNDC1 and miR-137 is downregulated. FUNDC1 binds PGAM5 phosphatase which cleaves the remaining Ser13 phosphorylation on the first. Interestingly, PGAM5 and CK2 antagonistically bind on FUNDC1. Stoichiometric alterations on FUNDC1 upon hypoxia render its binding affinity for PGAM5 stronger than for CK2. Concomitantly, owing to BCL-xL degradation in response to hypoxia PGAM5 is not trapped on the OMM anymore. Complete dephosphorylation of FUNDC1 triggers LC3 binding and mitophagy onset. Under conditions of prolonged or severe hypoxia, additional mechanisms further increase mitophagy rates. For example, MARCH5 dimerization blocks FUNDC1 degradation and the levels of the second increase. Besides, FUNDC1 phosphorylation at Ser17 by ULK1 increases its affinity for LC3 and last, the CNX-dependent FUNDC1 accumulation in the MAM further boosts mitophagy. This is also facilitated by both DNM1L recruitment and increased affinity of FUNDC1 for LC3 binding. In the bottom half of the Figure, processes that take place under normoxia are illustrated and in the top half, processes under hypoxia. The axis in the left part of the Figure is representative of the available oxygen concentration. Events in the top half (hypoxia) are presented in a specific sequence; when moving from left to right, the severity or duration of the hypoxic event is increased.
Figure 2 Regulation of FUNDC1-mediated mitophagy in normoxia versus hypoxia. FUNDC1 is inactivated upon normoxia by two phosphorylation events at Tyr18 and Ser13. Phosphorylation at these sites is accomplished by the Src and CK2 kinases, respectively and renders the LIR motif of FUNDC1 inaccessible to LC3. Also, OPA1 binds FUNDC1 in the intermembrane space, promoting mitochondrial fusion. miR-137, which targets the 3′ UTR of FUNDC1 mRNA is upregulated upon normoxia, thus blocking protein synthesis. In parallel, BCL-xL binds PGAM5 and renders it dormant and additionally, the E3 ubiquitin ligase physically interacts with FUNDC1, ubiquitinates it and triggers its proteasomal degradation. This effect is also evident just at the onset of hypoxia. Following, Src kinase is inactivated through phosphorylation on its Tyr416 residue. Src inactivation further blocks Tyr18 phosphorylation on FUNDC1. Moreover, OPA1 dissociates from FUNDC1 and miR-137 is downregulated. FUNDC1 binds PGAM5 phosphatase which cleaves the remaining Ser13 phosphorylation on the first. Interestingly, PGAM5 and CK2 antagonistically bind on FUNDC1. Stoichiometric alterations on FUNDC1 upon hypoxia render its binding affinity for PGAM5 stronger than for CK2. Concomitantly, owing to BCL-xL degradation in response to hypoxia PGAM5 is not trapped on the OMM anymore. Complete dephosphorylation of FUNDC1 triggers LC3 binding and mitophagy onset. Under conditions of prolonged or severe hypoxia, additional mechanisms further increase mitophagy rates. For example, MARCH5 dimerization blocks FUNDC1 degradation and the levels of the second increase. Besides, FUNDC1 phosphorylation at Ser17 by ULK1 increases its affinity for LC3 and last, the CNX-dependent FUNDC1 accumulation in the MAM further boosts mitophagy. This is also facilitated by both DNM1L recruitment and increased affinity of FUNDC1 for LC3 binding. In the bottom half of the Figure, processes that take place under normoxia are illustrated and in the top half, processes under hypoxia. The axis in the left part of the Figure is representative of the available oxygen concentration. Events in the top half (hypoxia) are presented in a specific sequence; when moving from left to right, the severity or duration of the hypoxic event is increased.CC BY · PubMed Central
Figure 3 Regulation of BNIP3/NIX-mediated mitophagy in normoxia versus hypoxia. Under normoxia, BNIP3/NIX exhibit basal expression due to HIF-1 degradation in the cytoplasm and hence decreased transcriptional activity. Besides, the OMM localized BCL-xL and Bcl-2 tether Beclin and finally block autophagy induction. In addition, Rheb is free of BNIP3 binding, thus activates mTOR and blocks autophagy induction. Moreover, miR-137, which binds on the 3′ UTR of BNIP3/NIX and suppresses their expression, increases; and last, Drp1 dissipates in the cytoplasm. Upon hypoxia, on the other hand, BNIP3/NIX are highly expressed in a HIF-1-dependent manner. Increased BNIP3/NIX abundance on the OMM triggers Bcl-2/Beclin and BCL-xL /Beclin complex dissociation. Particularly, BNIP3 and NIX are bound on either BCL-xL or Bcl-2, rendering Beclin free to trigger autophagy induction. General autophagy induction could in turn trigger mitophagy. Additionally, BNIP3/NIX accumulation on the OMM triggers mitochondrial dysfunction and membrane depolarization. This leads to excessive ROS production, which can also activate general autophagy. Moreover, BNIP3 binds Rheb, thus diminishes the amount of “free”/cytoplasmic Rheb-GTP and inactivates mTOR, inducing again general autophagy. Concomitantly, BNIP3/NIX phosphorylation and dimerization triggers LC3 binding and finally mitophagy induction. It is also conceivable that Drp1 triggers mitochondrial fragmentation by translocating on the OMM. miR-137 levels drop. In the bottom half of the Figure, processes that take place under normoxia are illustrated and in the top half, processes under hypoxia. The axis in the left part of the Figure is representative of the available oxygen concentration.
Figure 3 Regulation of BNIP3/NIX-mediated mitophagy in normoxia versus hypoxia. Under normoxia, BNIP3/NIX exhibit basal expression due to HIF-1 degradation in the cytoplasm and hence decreased transcriptional activity. Besides, the OMM localized BCL-xL and Bcl-2 tether Beclin and finally block autophagy induction. In addition, Rheb is free of BNIP3 binding, thus activates mTOR and blocks autophagy induction. Moreover, miR-137, which binds on the 3′ UTR of BNIP3/NIX and suppresses their expression, increases; and last, Drp1 dissipates in the cytoplasm. Upon hypoxia, on the other hand, BNIP3/NIX are highly expressed in a HIF-1-dependent manner. Increased BNIP3/NIX abundance on the OMM triggers Bcl-2/Beclin and BCL-xL /Beclin complex dissociation. Particularly, BNIP3 and NIX are bound on either BCL-xL or Bcl-2, rendering Beclin free to trigger autophagy induction. General autophagy induction could in turn trigger mitophagy. Additionally, BNIP3/NIX accumulation on the OMM triggers mitochondrial dysfunction and membrane depolarization. This leads to excessive ROS production, which can also activate general autophagy. Moreover, BNIP3 binds Rheb, thus diminishes the amount of “free”/cytoplasmic Rheb-GTP and inactivates mTOR, inducing again general autophagy. Concomitantly, BNIP3/NIX phosphorylation and dimerization triggers LC3 binding and finally mitophagy induction. It is also conceivable that Drp1 triggers mitochondrial fragmentation by translocating on the OMM. miR-137 levels drop. In the bottom half of the Figure, processes that take place under normoxia are illustrated and in the top half, processes under hypoxia. The axis in the left part of the Figure is representative of the available oxygen concentration.CC BY · PubMed Central

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Authors
Daskalaki, I., Gkikas, I., & Tavernarakis, N.
Affiliations
University of Crete (GR)
Corresponding author
Tavernarakis, Nektarios
ORCID
Venue
Frontiers in Cell and Developmental Biology
Publisher
Frontiers Media SA
Published
2018-09-10
Volume
6
Pages
104-104
ISSN
2296-634X (ISSN-L)
DOI
10.3389/fcell.2018.00104
PMC
PMC6139351
OpenAlex
W2890767393
Cited by
188
References
216
Citations by year
2026: 17 · 2025: 20 · 2024: 21 · 2023: 19 · 2022: 31 · 2021: 39 · 2020: 22 · 2019: 15 · 2018: 3
FWCI
2.82
Type
journal article
Language
en
Open access
Licence
Locations
  • Frontiers in Cell and Developmental Biology (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • European Commission
  • H2020 European Research Council (695190, 737599)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Autophagy in Disease and Therapy
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
Keywords
hypoxia, selective autophagy, cancer, hypoxia-inducible factor, unfolded protein response, mTOR, cancer metabolism, mitophagy, pexophagy, lipophagy, nucleophagy, metastasis, tumor cell survival

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