bims-noxint Biomed News
on NADPH oxidases in tumorigenesis
Issue of 2020‒09‒13
three papers selected by
Laia Caja Puigsubira
Uppsala University


  1. Cell Signal. 2020 Sep 02. pii: S0898-6568(20)30244-8. [Epub ahead of print] 109767
    Zhang L, Wu Y, Wu J, Zhou M, Li D, Wan X, Jin F, Wang Y, Lin W, Zha X, Liu Y.
      Tumor suppressor gene PTEN is frequently mutated in a wide variety of cancers. However, the downstream targets or signal transduction pathways of PTEN remain not fully understood. By analyzing Pten-null mouse embryonic fibroblasts (MEFs) cell lines and their isogenic counterparts, we showed that loss of PTEN led to increased cyclooxygenase2 (COX2) expression in an AKT-independent manner. Moreover, we demonstrated that PTEN deficiency promotes the transcription of COX2 via upregulation of the transcription factor Krüppel-like factor 5 (KLF5). Knocked down the expression of COX2 suppressed proliferation, migration and tumoral growth of Pten-null cells. Further experiments revealed that COX2 enhanced Pten-null MEFs growth and migration through upregulation of NADPH oxidase 4 (NOX4). In addition, MK-2206, a specific inhibitor of AKT, in combination with celecoxib, a COX2 inhibitor, strongly inhibited Pten-deficient cell growth. We concluded that KLF5/COX2/NOX4 signaling pathway is critical for cell growth and migration caused by the loss of PTEN, and the combination of MK-2206 and celecoxib may be an effective new approach to treating PTEN deficiency related tumors.
    Keywords:  COX2; Celecoxib; KLF5; MK-2206; PTEN
    DOI:  https://doi.org/10.1016/j.cellsig.2020.109767
  2. Oncol Rep. 2020 Sep 07.
    Wang X, Tao G, Huang D, Liang S, Zheng D.
      Colorectal cancer (CRC) is a common malignancy globally. The aim of the present study was to explore the role and the working mechanism of circular RNA NADPH oxidase 4 (circNOX4; circBase ID, hsa_circ_0023990) in CRC. Reverse transcription‑quantitative (RT‑q)PCR was used to examine the expression of circNOX4, NOX4 mRNA and microRNA (miR)‑485‑5p in CRC tissues and cell lines. 3‑(4,5‑Dimethylthiazol‑2‑yl)‑2,5‑diphenyltetrazolium bromide and Transwell assays were performed to analyze CRC cell viability and motility. The glycolytic ability of CRC cells was assessed by measuring glucose consumption, lactate production, extracellular acidification and O2 consumption rates using commercial kits. The starBase database was used to predict the targets of circNOX4 and miR‑485‑5p, and the interaction was confirmed by dual‑luciferase reporter and RNA immunoprecipitation assays. A murine xenograft model was established to verify the role of circNOX4 in CRC in vivo. The results demonstrated that the expression of circNOX4 was upregulated in CRC tissues and cell lines compared with that in adjacent normal tissues and a normal colon epithelial cell line, respectively. The expression of circNOX4 was negatively associated with the prognosis of patients with CRC. CircNOX4 silencing suppressed the proliferation, migration, invasion and glycolysis of CRC cells. miR‑485‑5p was identified as a target of circNOX4. CircNOX4 promoted CRC progression by sponging miR‑485‑5p. miR‑485‑5p was demonstrated to bind to the 3' untranslated region (UTR) of CDC28 protein kinase regulatory subunit 1B (CKS1B). miR‑485‑5p overexpression‑mediated malignant properties of CRC cells were partly reversed by the transfection with the CKS1B overexpression plasmid. CircNOX4 silencing restrained the CRC xenograft growth in vivo. Collectively, the results of the present study demonstrated that circNOX4 may serve an oncogenic role in CRC by promoting the proliferation, migration, invasion and glycolysis of CRC cells via the miR‑485‑5p/CKS1B axis.
    DOI:  https://doi.org/10.3892/or.2020.7758
  3. Int J Mol Sci. 2020 Sep 03. pii: E6416. [Epub ahead of print]21(17):
    Cheon YH, Lee CH, Jeong DH, Kwak SC, Kim S, Lee MS, Kim JY.
      Receptor activator of NF-κB ligand (RANKL) induces generation of intracellular reactive oxygen species (ROS), which act as second messengers in RANKL-mediated osteoclastogenesis. Dual oxidase maturation factor 1 (Duoxa1) has been associated with the maturation of ROS-generating enzymes including dual oxidases (Duox1 and Duox2). In the progression of osteoclast differentiation, we identified that only Duoxa1 showed an effective change upon RANKL stimulation, but not Duox1, Duox2, and Duoxa2. Therefore, we hypothesized that Duoxa1 could independently act as a second messenger for RANKL stimulation and regulate ROS production during osteoclastogenesis. Duoxa1 gradually increased during RANKL-induced osteoclastogenesis. Using siRNA or retrovirus transduction, we found that Duoxa1 regulated RANKL-stimulated osteoclast formation and bone resorption positively. Furthermore, knockdown of Duoxa1 decreased the RANKL-induced ROS production. During Duoxa1-related control of osteoclastogenesis, activation of tumor necrosis factor receptor-associated factor 6 (TRAF6)-mediated early signaling molecules including MAPKs, Akt, IκB, Btk, Src and PLCγ2 was affected, which sequentially modified the mRNA or protein expression levels of key transcription factors in osteoclast differentiation, such as c-Fos and NFATc1, as well as mRNA expression of osteoclast-specific markers. Overall, our data indicate that Duoxa1 plays a crucial role in osteoclastogenesis via regulating RANKL-induced intracellular ROS production and activating TRAF6-mediated signaling.
    Keywords:  Duoxa1; RANKL; ROS; TRAF6; osteoclast
    DOI:  https://doi.org/10.3390/ijms21176416