Activators of protein kinase C selectively mediate cellular cytotoxicity to hypoxic cells and not aerobic cells

Koong, Albert C.; Chen, Eric; Kim, Charlotte Y.; Giaccia, Amato J.

doi:10.1016/0360-3016(94)90272-0

Cited by 12 publications

(3 citation statements)

References 24 publications

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“…This hypothesis is supported by preliminary data from our lab, but also from previously published study by Koong et al showing increased sensitivity of tumor cells to thapsigargin treatments under hypoxia [124]. Recent data showing that hypoxia activates the UPR as a mechanism of tumor cell adaptation to low energy availability and that UPR activation promotes tumor growth and increased resistance to certain genotoxic chemotherapeutic agents, provide yet another mechanism by which hypoxia manifests these pro-tumorigenic properties.…”

Section: Discussionsupporting

confidence: 86%

ER Stress, Hypoxia Tolerance and Tumor Progression

Koumenis¹

2006

CMM

212

143

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The development of chronic and fluctuating hypoxic regions in tumors has profound consequences for malignant progression, response to therapy and overall patient survival. Understanding the events involved in hypoxia tolerance will offer new opportunities for antitumor modalities. A universal response of tumor cells to hypoxia is a rapid and substantial decrease in the rates of macromolecular synthesis. Hypoxia induces phosphorylation of the translation initiation factor eIF2alpha on Ser51 via activation of the endoplasmic reticulum (ER) resident kinase PERK and that this modification is required for the rapid downregulation of global protein synthesis by this hypoxic stress. PERK-dependent phosphorylation of eIF2alpha is one component of the Unfolded Protein Response (UPR), a coordinated program that promotes cell survival under conditions of ER stress. Inactivation of PERK or eIF2alpha phosphorylation impairs cell survival under hypoxia, and transformed cells with inactivating PERK or eIF2alpha mutations form tumors in nude mice that are slower growing, and have higher levels of apoptosis in hypoxic areas compared to tumors with an intact UPR. Expression of the transcription factor ATF4, a downstream effector of eIF2alpha phosphorylation, is also upregulated by hypoxia in vitro and in human tumors and increases hypoxia tolerance. A second UPR pathway mediated by activation of IRE1 and its downstream target XBP1 is also required for hypoxia tolerance in vitro and for tumor growth. These results reveal a critical role for UPR activation for tumor cell resistance to hypoxia and tumor growth promotion and suggest that the UPR may be an attractive target for anti-tumor modalities.

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Section: Discussionsupporting

confidence: 86%

ER Stress, Hypoxia Tolerance and Tumor Progression

Koumenis¹

2006

CMM

212

143

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“…Since its discovery in the early 1990s, HIF-1 has rapidly attracted interest for its involvement in fundamental biological processes -such as cardiovascular development [36], tumour metabolism [37] and stem cell differentiation [38]. Its role in regulating the transcriptional response to oxygen deprivation has made it a potential therapeutic target [39].…”

Section: Discussionmentioning

confidence: 99%

NFκB and HIF display synergistic behaviour during hypoxic inflammation

Brüning

Fitzpatrick

Frank

et al. 2011

Cell. Mol. Life Sci.

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The oxygen-sensitive transcription factor Hypoxia Inducible Factor (HIF) is a key regulator of gene expression during adaptation to hypoxia. Crucially, inflamed tissue often displays regions of prominent hypoxia. Recent studies have shown HIF signalling is intricately linked to that of the pro-inflammatory transcription factor Nuclear factor kappa B (NF!B) during hypoxic inflammation. Here we describe the relative temporal contributions of each to hypoxia-induced inflammatory gene expression and investigate the level of crosstalk between the two pathways using a novel Gaussia princeps luciferase (Gluc) reporter system. Under the control of an active promoter, Gluc is expressed and secreted into the cell culture media, where it can be sampled and measured over time. Thus Gluc constructs under the control of either HIF or NF!B were used to resolve their temporal transcriptional dynamics in response to hypoxia and to cytokine stimuli respectively. We also investigated the interactions between HIF and NF!B activities using a construct containing the sequence from the promoter of the inflammatory gene cyclooxygenase 2 (COX-2), which includes functionally active binding sites for both HIF and NF!B. Finally, based on our experimental data, we constructed a mathematical model of the binding affinities of HIF and NF!B to their respective response elements to analyse transcriptional crosstalk. Taken together, these data reveal distinct temporal HIF and NF!B transcriptional activities in response to hypoxic inflammation. Furthermore, we demonstrate synergistic activity between these two transcription factors on the regulation of the COX-2 promoter, implicating a coordinated role for both HIF and NF!B in the expression of COX-2 in hypoxic inflammation.

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“…oxidative stress such as JNK/SAP kinase and p38 kinase. Membrane-associated Src kinase and protein kinase C (PKC) are involved since c-Src is phosphorylated early after hypoxia stress (57) and inhibitors of PKC decrease the activity of this pathway (58). The hypoxia activation of NF-sB proceeds through c-Ras and c-Raf and then diverges from the conventional growth factor pathway (57,59).…”

Section: Hypoxia Sensing and Signal Transductionmentioning

confidence: 99%