The Role of the Hypoxia-Related Unfolded Protein Response (UPR) in the Tumor Microenvironment

Bartoszewska, Sylwia; Collawn, James F.; Bartoszewski, Rafał

doi:10.3390/cancers14194870

Cited by 20 publications

(17 citation statements)

References 330 publications

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“…Although changing HIF-α isoform dependency during hypoxia has been recognized both in endothelial and cancer cells [ 4 , 17 , 39 , 40 ] as an important regulator of the adaptive response and a potential therapy target, the mechanisms responsible for the hypoxic HIF-1α protein destabilization under low oxygen pressure were less clear. Previous studies in cancer cells have identified hypoxia-associated factor (HAF), that selectively binds and degrades HIF-1α in an oxygen-dependent manner, whereas its binding to HIF-2α selectively increases this factor transactivation [ 41 ].…”

Section: Discussionmentioning

confidence: 99%

The transition from HIF-1 to HIF-2 during prolonged hypoxia results from reactivation of PHDs and HIF1A mRNA instability

et al. 2022

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The hypoxia-inducible factors (HIF) are transcription factors that activate the adaptive hypoxic response when oxygen levels are low. The HIF transcriptional program increases oxygen delivery by inducing angiogenesis and by promoting metabolic reprograming that favors glycolysis. The two major HIFs, HIF-1 and HIF-2, mediate this response during prolonged hypoxia in an overlapping and sequential fashion that is referred to as the HIF switch. Both HIF proteins consist of an unstable alpha chain and a stable beta chain. The instability of the alpha chains is mediated by prolyl hydroxylase (PHD) activity during normoxic conditions, which leads to ubiquitination and proteasomal degradation of the alpha chains. During normoxic conditions, very little HIF-1 or HIF-2 alpha–beta dimers are present because of PHD activity. During hypoxia, however, PHD activity is suppressed, and HIF dimers are stable. Here we demonstrate that HIF-1 expression is maximal after 4 h of hypoxia in primary endothelial cells and then is dramatically reduced by 8 h. In contrast, HIF-2 is maximal at 8 h and remains elevated up to 24 h. There are differences in the HIF-1 and HIF-2 transcriptional profiles, and therefore understanding how the transition between them occurs is important and not clearly understood. Here we demonstrate that the HIF-1 to HIF-2 transition during prolonged hypoxia is mediated by two mechanisms: (1) the HIF-1 driven increase in the glycolytic pathways that reactivates PHD activity and (2) the much less stable mRNA levels of HIF-1α (HIF1A) compared to HIF-2α (EPAS1) mRNA. We also demonstrate that the alpha mRNA levels directly correlate to the relative alpha protein levels, and therefore to the more stable HIF-2 expression during prolonged hypoxia.

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Section: Discussionmentioning

confidence: 99%

The transition from HIF-1 to HIF-2 during prolonged hypoxia results from reactivation of PHDs and HIF1A mRNA instability

et al. 2022

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“…Hoechst 33258 staining When ER stress persists, the unfolded protein response is insufficient to remove accumulated unfolded proteins or damaged organelles, and autophagy is activated [29]. When ER stress is too strong or lasts too long, overactivation of autophagy eventually leads to apoptosis [30]. GRP78 overexpression and UPR components have been implicated in the development of malignant gliomas with aggressive phenotypes, whereas ER stress predisposes glioma cells to undergo apoptosis [31][32][33].…”

Section: Discussionmentioning

confidence: 99%

Saikosaponin D Inducing Apoptosis and Autophagy through the Activation of Endoplasmic Reticulum Stress in Glioblastoma

Liu

Guan

Liu

et al. 2022

BioMed Research International

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Saikosaponin D (SSD), a saponin derivative, is extracted from Bupleurum falcatum. It exhibits an inhibitory effect on a number of tumor cells and is relatively safe when used at therapeutic doses. However, its effects on glioblastoma multiforme (GBM) have not been fully explored. This study is aimed at investigating the cytotoxic effects of SSD in GBM cell lines. SSD induces apoptosis and autophagy by activating endoplasmic reticulum (ER) stress in GBM cells. GBM cell proliferation activity and morphology were observed using the Cell Counting Kit-8 assay and hematoxylin and eosin staining. Hoechst 33258 fluorescence staining and flow cytometry were performed to assess apoptosis. Western blotting and immunocytochemical staining were used to detect protein expression and distribution. SSD significantly inhibited the proliferation of RG-2, U87-MG, and U251 cells in a dose-dependent manner, and the proportion of apoptotic cells increased significantly. Additionally, the expressions of ER-, apoptosis-, and autophagy-related proteins were significantly upregulated and distributed in the cytoplasm and nucleus. Therefore, SSD may be considered a novel treatment option for GBM. This study demonstrated the anti-GBM effect of SSD from the perspectives of cell apoptosis and autophagy.

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“…Although changing HIF-α isoform dependency during hypoxia has been recognized both in endothelial and cancer cells [4,17,39,40] as an important regulator of the adaptive response and a potential therapy target, the mechanisms responsible for the hypoxic HIF-1α protein destabilization under low oxygen pressure were less clear. Previous studies in cancer cells have identified hypoxia-associated factor (HAF), that selectively binds and degrades HIF-1α in an oxygen-dependent manner, whereas its binding to HIF-2α selectively increases this factor transactivation [41].…”

Section: Discussionmentioning

confidence: 99%

The transition from HIF-1 to HIF-2 during prolonged hypoxia results from reactivation of PHDs and HIF1A mRNA instability

Jaśkiewicz

Moszyńska

Króliczewski

et al. 2022

Preprint

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The hypoxia-inducible factors (HIF) are transcription factors that activate the adaptive hypoxic response when oxygen levels are low. The HIF transcriptional program increases oxygen delivery by inducing angiogenesis and by promoting metabolic reprograming that favors glycolysis. The two major HIFs, HIF-1 and HIF-2, mediate this response during prolonged hypoxia in an overlapping and sequential fashion that is referred to as the HIF switch. Both HIF proteins consist of an unstable alpha chain and a stable beta chain. The instability of the alpha chains is mediated by prolyl hydroxylase (PHD) activity during normoxic conditions, which leads to ubiquitination and proteasomal degradation of the alpha chains. During normoxic conditions, very little HIF-1 or HIF-2 alpha-beta dimers are present because of PHD activity. During hypoxia, however, PHD activity is suppressed, and HIF dimers are stable. Here we demonstrate that HIF-1 expression is maximal after 4 hours of hypoxia in primary endothelial cells and then is dramatically reduced by 8 hours. In contrast, HIF-2 is maximal at 8 hours and remains elevated up to 24 hours. There are differences in the HIF-1 and HIF-2 transcriptional profiles, and therefore understanding how the transition between them occurs is important and not clearly understood. Here we demonstrate that the HIF-1 to HIF-2 transition during prolonged hypoxia is mediated by two mechanisms: (1) the HIF-1 driven increase in the glycolytic pathways that reactivates PHD activity and (2) the much less stable mRNA levels of HIF-1α (HIF1A) compared to HIF-2α (EPAS1) mRNA. We also demonstrate that the alpha mRNA levels directly correlate to the relative alpha protein levels, and therefore to the more stable HIF-2 expression during prolonged hypoxia.

show abstract

The Role of the Hypoxia-Related Unfolded Protein Response (UPR) in the Tumor Microenvironment

Cited by 20 publications

References 330 publications

The transition from HIF-1 to HIF-2 during prolonged hypoxia results from reactivation of PHDs and HIF1A mRNA instability

The transition from HIF-1 to HIF-2 during prolonged hypoxia results from reactivation of PHDs and HIF1A mRNA instability

Saikosaponin D Inducing Apoptosis and Autophagy through the Activation of Endoplasmic Reticulum Stress in Glioblastoma

The transition from HIF-1 to HIF-2 during prolonged hypoxia results from reactivation of PHDs and HIF1A mRNA instability

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