Abstract
Hypoxia is a phenomenon often arising in solid tumours, linked to aggressive malignancy, bad prognosis and resistance to therapy. Hypoxia-inducible factor-1 has been identified as a key mediator of cell and tissue adaptation to hypoxic conditions through transcriptional activation of many genes involved in glucose metabolism and other cancer-related processes, such as angiogenesis, cell survival and cell invasion. Cyclic adenosine 3′5′-monophosphate is one of the most ancient and evolutionarily conserved signalling molecules and the cAMP/PKA signalling pathway plays an important role in cellular adaptation to hypoxia. We have investigated possible new mechanisms behind hypoxic activation of the cAMP/PKA pathway. For the first time, we have shown that hypoxia induces transcriptional up-regulation of the system of adenylyl cyclases, enzymes responsible for cAMP production, in a panel of carcinoma cell lines of various origin. Our data prove functional relevance of the hypoxic increase of adenylyl cyclases VI and VII at least partially mediated by HIF-1 transcription factor. We have identified adenylyl cyclase VI and VII isoforms as mediators of cellular response to hypoxia, which led to the elevation of cAMP levels and enhanced PKA activity, with an impact on cell migration and pH regulation.
Highlights
Carbonic anhydrase IX (CA IX) is a HIF-1-induced metalloenzyme associated with solid tumours[2, 3]
CAMP is synthesised from adenosine triphosphate by adenylyl cyclases (ADCY) that are encoded by ten various genes (ADCY1-10)
The analysis of a panel of carcinoma cell lines (HeLa, C33a, RKO, and MCF7) cultured in normoxia (21% O2) and hypoxia (2% O2, 2% H2, 5%CO2, 91% N2) confirmed this finding. cyclic adenosine 3′5′-monophosphate (cAMP) production was significantly increased in all tested cell lines (Fig. 1A)
Summary
Carbonic anhydrase IX (CA IX) is a HIF-1-induced metalloenzyme associated with solid tumours[2, 3]. Our recent study revealed that phosphorylation of Thr[443] residue in the intracellular tail by the cyclic adenosine 3′5′-monophosphate (cAMP)-dependent protein kinase A (PKA) is required for CA IX activation[10]. A pivotal role in their activation is played by heterotrimeric G proteins transducing multiple extracellular signals through G protein-coupled receptors They receive signals e.g. from PKA, protein kinase C, calmodulin, calcineurin and various small molecules. Modern methods based on in situ measurements revealed its restricted diffusion inside signalling microdomains at the plasma membrane and other intracellular sites where cAMP is formed, degraded and localised closer to the place of action with the entire machinery of a unique composition, made up of ADCYs, phosphodiesterases (PDEs), A-kinase anchor proteins (AKAPs) and effector molecules, such as exchange proteins directly activated by cAMP (EPACs) and PKA19–21
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
