bims-noxint Biomed News
on NADPH oxidases in tumorigenesis
Issue of 2019‒04‒28
five papers selected by
Laia Caja Puigsubira
Uppsala University

  1. Biochem Pharmacol. 2019 Apr 23. pii: S0006-2952(19)30159-5. [Epub ahead of print]
    Ciriaci N, Andermatten RB, Razori MV, Schuck VS, Miszczuk GS, Medeot AC, Crocenzi FA, Roma MG, Barosso IR, Ruiz ML, Pozzi EJS.
      TNFα is a cytokine whose levels are increased in inflammatory pathologies that are associated with cholestasis. Endocytic internalization of Abcc2 (multidrug resistance-associated protein 2), a canalicular transporter of organic anions that is implicated in the clearance of clinically important drugs, is a phenomenon that occurs in inflammatory liver diseases, and it has been established that cytokines act as mediators. However, the intracellular mechanism involved in this effect remains unknown. The aim of the present work was to characterize the internalization of Abcc2 induced by TNFα and to study the role of ERK1/2 and reactive oxygen species as signaling mediators of transporter internalization. Using rat hepatocyte couplets, we found that TNFα (6.25 pg/ml) induced a decrease in Abcc2 activity estimated by the accumulation of the Abcc2 substrate glutathione methylfluorescein in the canalicular vacuole that was accompanied by internalization of Abcc2 from the canalicular membrane. Inhibition of MEK1/2 (upstream of ERK1/2) partially prevented TNFα effects on Abcc2 internalization and activity impairment. Reactive oxygen species (ROS) scavengers such as vitamin C and mannitol partially prevented both TNFα-induced decrease in Abcc2 activity and ERK1/2 phosphorylation. Apocynin, a NADPH oxidase inhibitor, prevented the increase in ROS and the phosphorylation of ERK1/2 produced by TNFα. Taken together, these results indicate that TNFα activates a pathway involving NADPH oxidase, ROS and MEK1/2-ERK1/2 that is partially responsible for the internalization of Abcc2. This internalization leads to an altered transport activity of Abcc2 that could impair drug disposal, enhancing drug toxicity in patients suffering from inflammatory liver diseases.
    Keywords:  ABC transporters; Cholestasis; Mrp2; NOX; ROS
  2. Artif Cells Nanomed Biotechnol. 2019 Dec;47(1): 1416-1422
    Wu P, Cao Y, Zhao R, Wang Y.
      Loss of the capacities of epidermal stem cells (ESCs) induced by ultraviolet-B (UV-B) irradiation has been widely associated with various skin diseases. Netrin-1, a member of the axonal guidance protein family, has displayed diverse biological functions in different types of cells and tissues, mediated by its specific receptor UNC-5 homolog B (UNC5b). In this study, we examined the physiological functions of netrin-1 and UNC5b in ESCs upon UV-B exposure. Our results indicate that UNC5b is expressed in ESCs, and its expression is upregulated in response to UV-B radiation. We found that treatment with netrin-1 prevented UV-B radiation-induced oxidative stress by reducing the generation of reactive oxygen species (ROS) and expression of NADPH oxidase 4 (NOX-4). Additionally, treatment with netrin-1 improved UV-B radiation-induced mitochondrial dysfunction by increasing mitochondrial membrane potential (MMP) levels and adenosine triphosphate (ATP) production. The presence of netrin-1 attenuated UV-B radiation-induced lactic dehydrogenase (LDH) release. UV-B exposure resulted in the loss of the capacities of ESCs by reducing the expressions of integrin β1 and Krt19, the two major ESC markers. Importantly, this process was prevented by netrin-1. Silencing of UNC5b abolished the effects of netrin-1 on the expression of integrin β1 and Krt19, suggesting that the effects of netrin-1 in maintaining the capacities of ESCs are dependent on UNC5b. Mechanistically, we found that the Wnt/β-catenin signalling may be involved. Our findings suggest that netrin-1 may serve as a therapeutic agent for the treatment of skin diseases.
    Keywords:  Epidermal stem cells; Wnt/β-catenin; netrin-1; skin; ultraviolet-B
  3. Circ Res. 2019 Apr 26.
    Calvier L, Boucher P, Herz J, Hansmann G.
      RATIONALE: Arterial remodeling, a hallmark of many cardiovascular pathologies including pulmonary arterial hypertension (PAH), is regulated by TGFβ1-TGFβ receptors and the antagonistic, vasoprotective BMPR2-PPARγ axis. However, it is unclear which factors drive detrimental TGFβ1 pathways in the hypertensive pulmonary vasculature.OBJECTIVE: We hypothesized that LDL receptor-related protein1 (LRP1) expression is decreased in PAH, leading to enhancement (disinhibition) of TGFβ1 signals, and that the PPARγ agonist pioglitazone can restore vascular homeostasis and prevent PAH resulting from LRP1 deletion in vascular smooth muscle cells (VSMC).
    METHODS AND RESULTS: Targeted deletion of LRP1 in VSMC (smLRP1-/-) in mice disinhibited TGFβ1-CTGF signaling, leading to spontaneous PAH and distal pulmonary arterial muscularization as assessed by closed-chest cardiac catheterization and anti-αSMA staining. Pioglitazone inhibited the canonical TGFβ1-CTGF axis in human pulmonary artery SMC (HPASMC) and smLRP1-/- main pulmonary artery (CTGF, NOX4), and reversed PAH in smLRP1-/- mice. TGFβ1 boosted pSmad3 in PASMC from smLRP1-/- mice vs. controls. Pioglitazone-activated PPARγ binds to Smad3 in HPASMC (co-immunoprecipitation), thereby blocking its phosphorylation and overriding LRP1 deficiency. Finally, mRNA and protein expression of LRP1 was decreased in pulmonary plexiform lesions of patients with endstage idiopathic PAH (laser capture microdissection, qPCR, immunoblotting). Downregulation of LRP1 protein was also demonstrated in explanted PASMC from PAH patients and accompanied by enhanced TGFβ1-pSmad3-CTGF signaling and increased TGFβ1-induced PASMC proliferation that was prevented by pioglitazone.
    CONCLUSIONS: Here, we identify LRP1 as an integrator of TGFβ1-mediated mechanisms that regulate vascular remodeling in mice and clinical PAH, and PPARγ as a therapeutic target that controls canonical TGFβ1 pathways. Hence, pharmacological PPARγ activation represents a promising new therapy for PAH patients who lack the vasoprotective LRP1 in VSMC.
    Keywords:  LDL receptor-related protein 1; LRP1; TGF-beta 1; vascular biology; vascular disease
  4. Biochem Biophys Res Commun. 2019 Apr 19. pii: S0006-291X(19)30713-2. [Epub ahead of print]
    Zhou P, Chen X, Li M, Tan J, Zhang Y, Yuan W, Zhou J, Wang G.
      Acute myeloid leukemia (AML) is a heterogeneous clonal hematopoietic malignancy with poor survival and frequent relapse. Recently, a posttranslational modification of proteins with small ubiquitin-like modifiers (SUMO) has been notably implicated in a wide spectrum of diseases, especially cancers. Ubc9, as the sole E2-conjugating enzyme in SUMOylation cascade, particularly has been associated with adverse clinical outcomes. 2-D08, a small molecular agent, functions by blocking the transfer of SUMO from the Ubc9 thioester to SUMO substrates without any effects on other individual steps in this process. However, both the effects and mechanisms of 2-D08 on AML cells are still unknown. In this study, we found that 2-D08 significantly suppressed cell viability and colony formation ability. Additionally, it induced mitochondrial-mediated apoptosis with dramatic accumulation of the reactive oxygen species (ROS), which could be almost completely rescued by the ROS scavenger N-acetylcysteine (NAC). Furthermore, we confirmed that the fatal accumulation of ROS was due to its aberrant generation instead of defective scavenging. In summary, our results suggest that 2-D08, as a specific SUMOylation inhibitor, induces ROS accumulation-mediated intrinsic apoptosis of AML cells possibly through deSUMOylation of NOX2. Therefore, 2-D08 might be a promising therapeutic agent for the treatment of AML in the future.
    Keywords:  2-D08; Acute myeloid leukemia; Apoptosis; NOX2; ROS; SUMOylation
  5. Oxid Med Cell Longev. 2019 ;2019 9296439
    Kim SL, Choi HS, Kim JH, Jeong DK, Kim KS, Lee DS.
      Cancer stem cells (CSCs) are known to mediate metastasis and recurrence and are therefore a promising therapeutic target. In this study, we found that dihydrotanshinone (DHTS) inhibits CSC formation. DHTS inhibited mammosphere formation in a dose-dependent manner and showed significant tumor growth inhibition in a xenograft model. This compound reduced the CD44high/CD24low- and aldehyde dehydrogenase- (ALDH-) expressing cell population and the self-renewal-related genes Nanog, SOX2, OCT4, C-Myc, and CD44. DHTS induced NOX5 activation by increasing calcium, and NOX5 activation induced reactive oxygen species (ROS) production. ROS production reduced the nuclear phosphorylation levels of Stat3 and secreted IL-6 levels in the mammospheres. DHTS deregulated the dynamic equilibrium from non-stem cancer cells to CSCs by dephosphorylating Stat3 and decreasing IL-6 secretion and inhibiting CSC formation. These novel findings showed that DHTS-induced ROS deregulated the Stat3/IL-6 pathway and induced CSC death. NOX5 activation by DHTS inhibits CSC formation through ROS/Stat3/IL-6 signaling, and DHTS may be a promising potential therapeutic agent against breast CSCs.