bims-noxint 2019-06-23 papers

Issue of 2019‒06‒23
three papers selected by
Laia Caja Puigsubira
Uppsala University

Cell Rep. 2019 Jun 18. pii: S2211-1247(19)30687-4. [Epub ahead of print]27(12): 3422-3432.e4

Acquired Resistance of EGFR-Mutated Lung Cancer to Tyrosine Kinase Inhibitor Treatment Promotes PARP Inhibitor Sensitivity.

Lynnette Marcar, Kankana Bardhan, Liliana Gheorghiu, Patrick Dinkelborg, Heike Pfäffle, Qi Liu, Meng Wang, Zofia Piotrowska, Lecia V Sequist, Kerstin Borgmann, Jeffrey E Settleman, Jeffrey A Engelman, Aaron N Hata, Henning Willers.

Lung cancers with oncogenic mutations in the epidermal growth factor receptor (EGFR) invariably acquire resistance to tyrosine kinase inhibitor (TKI) treatment. Vulnerabilities of EGFR TKI-resistant cancer cells that could be therapeutically exploited are incompletely understood. Here, we describe a poly (ADP-ribose) polymerase 1 (PARP-1) inhibitor-sensitive phenotype that is conferred by TKI treatment in vitro and in vivo and appears independent of any particular TKI resistance mechanism. We find that PARP-1 protects cells against cytotoxic reactive oxygen species (ROS) produced by nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX). Compared to TKI-naive cells, TKI-resistant cells exhibit signs of increased RAC1 activity. PARP-1 catalytic function is required for PARylation of RAC1 at evolutionarily conserved sites in TKI-resistant cells, which restricts NOX-mediated ROS production. Our data identify a role of PARP-1 in controlling ROS levels upon EGFR TKI treatment, with potentially broad implications for therapeutic targeting of the mechanisms that govern the survival of oncogene-driven cancer cells.

Keywords: EGFR mutation; Lung cancer; PARP-1; RAC1; oncogene; reactive oxygen species; tyrosine kinase inhibitor

DOI: https://doi.org/10.1016/j.celrep.2019.05.058

Diabetologia. 2019 Jun 20.

Endothelial or vascular smooth muscle cell-specific expression of human NOX5 exacerbates renal inflammation, fibrosis and albuminuria in the Akita mouse.

Jay C Jha, Aozhi Dai, Chet E Holterman, Mark E Cooper, Rhian M Touyz, Chris R Kennedy, Karin A M Jandeleit-Dahm.

AIMS/HYPOTHESIS: Excessive production of reactive oxygen species (ROS) plays a detrimental role in the progression of diabetic kidney disease (DKD). Renal oxidative stress activates proinflammatory cytokines, chemokines and profibrotic factors in DKD. Increased expression of the prooxidant enzyme NADPH oxidase (NOX) 5 in kidneys of diabetic individuals has been hypothesised to correlate with renal injury and progression of DKD. Since the gene encoding NOX5 is not expressed in the mouse genome, we examined the effect of inducible human NOX5 expression in renal cells, selectively in either endothelial cells or vascular smooth muscle cells (VSMCs)/mesangial cells in a model of insulin-deficient diabetes, the Akita mouse.METHODS: Renal structural injury, including glomerulosclerosis, mesangial expansion and extracellular matrix protein accumulation, as well as renal inflammation, ROS formation and albuminuria, were examined in the NOX5 transgenic Akita mouse model of DKD.
RESULTS: Expression of NOX5 in either endothelial cells or VSMCs/mesangial cells in diabetic Akita mice was associated with increased renal inflammation (monocyte chemoattractant protein-1, NF-κB and toll-like receptor-4) and glomerulosclerosis, as well as upregulation of protein kinase C-α and increased expression of extracellular matrix genes (encoding collagen III, fibronectin and α-smooth muscle actin) and proteins (collagen IV), most likely mediated via enhanced renal ROS production. The effect of VSMC/mesangial cell-specific NOX5 expression resulted in more pronounced renal fibrosis in comparison with endothelial cell-specific NOX5 expression in diabetic mice. In addition, albuminuria was significantly increased in diabetic VEcad+NOX5+ mice (1192 ± 194 μg/24 h) when compared with diabetic VEcad+NOX5- mice (770 ± 98 μg/24 h). Furthermore, the regulatory components of NOX5 activation, including heat shock protein 90 and transient receptor potential cation channel subfamily C member 6, were upregulated only in the presence of both NOX5 and diabetes.
CONCLUSIONS/INTERPRETATION: The findings from this study highlight the importance of NOX5 in promoting diabetes-related renal injury and provide the rationale for the development of a selective NOX5 inhibitor for the prevention and/or treatment of DKD.

Keywords: Akita mouse; Albuminuria; Diabetic kidney disease; Endothelial cells; Glomerulosclerosis; VSMCs/mesangial cells

DOI: https://doi.org/10.1007/s00125-019-4924-z

Redox Biol. 2019 Jun 04. pii: S2213-2317(19)30357-X. [Epub ahead of print]26 101233

Hippo kinases regulate cell junctions to inhibit tumor metastasis in response to oxidative stress.

Yang Wang, Juan Li, Ya Gao, Yue Luo, Hong Luo, Liang Wang, Yong Yi, Zengqiang Yuan, Zhi-Xiong Jim Xiao.

Reactive oxygen species (ROS) are key regulators in cell proliferation, survival, tumor initiation and development. However, the role of ROS in tumor metastasis is less clear. Here, we show that oxidative stress inhibited tumor metastasis via activation of Hippo kinase MST1/2, which led to the phosphorylation and nuclear accumulation of FoxO3a, resulting in upregulation of ΔNp63α expression and suppression of cell migration independent of YAP. Strikingly, while loss of MST1 led to and disruption of cell-cell junction exemplified by reduced E-cadherin expression, resulting in scattered cell growth, loss of MST2 led to disruption of cell-matrix adhesion as evidenced by reduced integrin β4, resulting in increased cell migration and tumor metastasis. Furthermore, expression of MST1 and MST2 was down-regulated in human breast carcinoma. Furthermore, oxidative stress inhibited HER2-or PI3K-mediated tumor metastasis via the MST2-FoxO3a-ΔNp63α pathway. Together, these results that this noncanonical Hippo MST2-FoxO3a-ΔNp63α pathway may play a critical role in ROS-mediated regulation of cell migration and tumor metastasis.

Keywords: Cell-cell junction; Cell-matrix adhesion; Hippo kinase; Metastasis; Np63α; Δ

DOI: https://doi.org/10.1016/j.redox.2019.101233