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Superoxide anion radicals induce IGF-1 resistance through concomitant activation of PTP1B and PTEN.

ABSTRACT: The evolutionarily conserved IGF-1 signalling pathway is associated with longevity, metabolism, tissue homeostasis, and cancer progression. Its regulation relies on the delicate balance between activating kinases and suppressing phosphatases and is still not very well understood. We report here that IGF-1 signalling in vitro and in a murine ageing model in vivo is suppressed in response to accumulation of superoxide anions (O2?-) in mitochondria, either by chemical inhibition of complex I or by genetic silencing of O2?--dismutating mitochondrial Sod2. The O2?--dependent suppression of IGF-1 signalling resulted in decreased proliferation of murine dermal fibroblasts, affected translation initiation factors and suppressed the expression of ?1(I), ?1(III), and ?2(I) collagen, the hallmarks of skin ageing. Enhanced O2?- led to activation of the phosphatases PTP1B and PTEN, which via dephosphorylation of the IGF-1 receptor and phosphatidylinositol 3,4,5-triphosphate dampened IGF-1 signalling. Genetic and pharmacologic inhibition of PTP1B and PTEN abrogated O2?--induced IGF-1 resistance and rescued the ageing skin phenotype. We thus identify previously unreported signature events with O2?-, PTP1B, and PTEN as promising targets for drug development to prevent IGF-1 resistance-related pathologies.

SUBMITTER: Singh K

PROVIDER: S-EPMC4309668 | biostudies-literature | 2015 Jan

REPOSITORIES: biostudies-literature

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Superoxide anion radicals induce IGF-1 resistance through concomitant activation of PTP1B and PTEN.

Singh Karmveer K Maity Pallab P Krug Linda L Meyer Patrick P Treiber Nicolai N Lucas Tanja T Basu Abhijit A Kochanek Stefan S Wlaschek Meinhard M Geiger Hartmut H Scharffetter-Kochanek Karin K

EMBO molecular medicine 20150101 1

The evolutionarily conserved IGF-1 signalling pathway is associated with longevity, metabolism, tissue homeostasis, and cancer progression. Its regulation relies on the delicate balance between activating kinases and suppressing phosphatases and is still not very well understood. We report here that IGF-1 signalling in vitro and in a murine ageing model in vivo is suppressed in response to accumulation of superoxide anions (O2∙-) in mitochondria, either by chemical inhibition of complex I or by ...[more]

PMID: 25520316

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Project description:BackgroundThe urokinase plasminogen activator receptor (uPAR) is associated with poor prognosis in oral squamous cell carcinoma (OSCC), and increased expression of uPAR is often found at the invasive tumour front. The aim of the current study was to elucidate the role of uPAR in invasion and metastasis of OSCC, and the effects of various tumour microenvironments in these processes. Furthermore, we wanted to study whether the cells' expression level of uPAR affected the activity of gelatinolytic enzymes.MethodsThe Plaur gene was both overexpressed and knocked-down in the murine OSCC cell line AT84. Tongue and skin tumours were established in syngeneic mice, and cells were also studied in an ex vivo leiomyoma invasion model. Soluble factors derived from leiomyoma tissue, as well as purified extracellular matrix (ECM) proteins, were assessed for their ability to affect uPAR expression, glycosylation and cleavage. Activity of gelatinolytic enzymes in the tissues were assessed by in situ zymography.ResultsWe found that increased levels of uPAR did not induce tumour invasion or metastasis. However, cells expressing low endogenous levels of uPAR in vitro up-regulated uPAR expression both in tongue, skin and leiomyoma tissue. Various ECM proteins had no effect on uPAR expression, while soluble factors originating from the leiomyoma tissue increased both the expression and glycosylation of uPAR, and possibly also affected the proteolytic processing of uPAR. Tumours with high levels of uPAR, as well as cells invading leiomyoma tissue with up-regulated uPAR expression, all displayed enhanced activity of gelatinolytic enzymes.ConclusionsAlthough high levels of uPAR are not sufficient to induce invasion and metastasis, the activity of gelatinolytic enzymes was increased. Furthermore, several tumour microenvironments have the capacity to induce up-regulation of uPAR expression, and soluble factors in the tumour microenvironment may have an important role in the regulation of posttranslational modification of uPAR.

Project description:The unique ability of nitrone spin traps to detect and characterize transient free radicals by electron paramagnetic resonance (EPR) spectroscopy has fueled the development of new spin traps with improved properties. Among a variety of free radicals in chemical and biological systems, superoxide radical anion (O(2)(•-)) plays a critical role as a precursor to other more oxidizing species such as hydroxyl radical (HO(•)), peroxynitrite (ONOO(-)), and hypochlorous acid (HOCl), and therefore the direct detection of O(2)(•-) is important. To overcome the limitations of conventional cyclic nitrones, that is, poor reactivity with O(2)(•-), instability of the O(2)(•-) adduct, and poor cellular target specificity, synthesis of disubstituted nitrones has become attractive. Disubstituted nitrones offer advantages over the monosubstituted ones because they allow bifunctionalization of spin traps, therefore accommodating all the desired spin trap properties in one molecular design. However, because of the high number of possible disubstituted analogues as candidate, a systematic computational study is needed to find leads for the optimal spin trap design for biconjugation. In this paper, calculation of the energetics of O(2)(•-) and HO(2)(•) adduct formation from various disubstituted nitrones at PCM/B3LYP/6-31+G(d,p)//B3LYP/6-31G(d) level of theory was performed to determine the most favorable disubstituted nitrones for this reaction. In addition, our results provided general trends of radical reactivity that is dependent upon but not exclusive to the charge densities of nitronyl-C, the position of substituents including stereoselectivities, and the presence of intramolecular H-bonding interaction. Unusually high exoergic ?G(298K,aq)'s for O(2)(•-) and HO(2)(•) adduct formation were predicted for (3S,5S)-5-methyl-3,5-bis(methylcarbamoyl)-1-pyrroline N-oxide (11-cis) and (4S,5S)-5-dimethoxyphosphoryl-5-methyl-4-ethoxycarbonyl-1-pyrroline N-oxide (29-trans) with ?G(298K,aq) = -3.3 and -9.4 kcal/mol, respectively, which are the most exoergic ?G(298K,aq) observed thus far for any nitrone at the level of theory employed in this study.

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Superoxide anion radicals induce IGF-1 resistance through concomitant activation of PTP1B and PTEN.

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Superoxide anion radicals induce IGF-1 resistance through concomitant activation of PTP1B and PTEN.

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