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. 2022 Oct 5;14(19):4870. doi: 10.3390/cancers14194870

Table 1.

The crosstalk between UPR and hypoxia signaling.

UPR Hypoxia Molecular Background Ref.
General induction of UPR including BiP expression Anoxia, acute extreme hypoxia, mild hypoxia (chronic), intermittent hypoxia

  1. CEMIP induces BIP expression;

  2. ERK/PKC activates UPR;

  3. HIF-1 through VEGFRs and PLC activates UPR.

  1. [65,146,193]

  2. [184]

  3. [229,230]
Activation of PERK signaling Anoxia, acute hypoxia, moderate hypoxia (chronic), intermittent hypoxia

  1. PERK activation inhibits HIF-1α translation;

  2. PERK induces CA9 expression;

  3. ATF4 reduces hypoxia-related damage and supports maintaining a redox balance and mitochondrial homeostasis;

  4. ATF4 destabilizes PHD3 to support HIF-1α accumulation;

  5. CHOP limits NOS3 activity;

  6. PERK/ATF4 limit EPO expression.

  1. [201]

  2. [106,203]

  3. [115,116,117,118,182]

  4. [202]

  5. [210]

  6. [58]
Activation of IRE1 signaling Anoxia, acute hypoxia, moderate hypoxia (chronic), intermittent hypoxia

  1. Acute hypoxia inhibits IRE1 and reduce XBP1s levels;

  2. IRE1 activity is necessary for maintaining proper HIF-1α expression;

  3. During prolonged hypoxia, XBP1s induces miR-153 to reduce HIF-1α;

  4. XBP1s interacts with HIF-1α to cooperatively stimulate expression of GLUT1 and LDHA.

  1. [222]

  2. [223]

  3. [215,216]

  4. [146,193,217]
ATF6 Anoxia, acute hypoxia, moderate hypoxia (chronic), intermittent hypoxia Along with ATF4 and XBP1 supports expression of VEGF. [231,232,233,234,235,236,237,238,239,240,241,242]