Acquisition of the Metastatic Phenotype Is Accompanied by H2O2-Dependent Activation of the p130Cas Signaling Complex

Hempel, Nadine; Bartling, Toni R.; Mian, Badar M.; Melendez, J. Andrés

doi:10.1158/1541-7786.mcr-12-0478

Cited by 27 publications

(47 citation statements)

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“…2 and 3). This suggests that the redox mediated increase in p130cas phosphorylation enhances p130cas protein stability [7]. Dephosphorylation has previously been shown to enhance p130cas degradation [23] and regulation of p130cas phosphorylation by phosphatases appears to be an important regulatory mechanism of its function [18].…”

Section: Discussionmentioning

confidence: 97%

Intracellular redox status controls membrane localization of pro- and anti-migratory signaling molecules

Hempel

Melendez

2014

Redox Biology

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Shifts in intracellular Reactive Oxygen Species (ROS) have been shown to contribute to carcinogenesis and to tumor progression. In addition to DNA and cell damage by surges in ROS, sub-lethal increases in ROS are implicated in regulating cellular signaling that enhances pro-metastatic behavior. We previously showed that subtle increases in endogenous H2O2 regulate migratory and invasive behavior of metastatic bladder cancer cells through phosphatase inhibition and consequential phosphorylation of p130cas, an adapter of the FAK signaling pathway. We further showed that enhanced redox status contributed to enhanced localization of p130cas to the membrane of metastatic cells. Here we show that this signaling complex can similarly be induced in a redox-engineered cell culture model that enables regulation of intracellular steady state H2O2 level by enforced expression of superoxide dismutase 2 (Sod2) and catalase. Expression of Sod2 leads to enhanced p130cas phosphorylation in HT-1080 fibrosarcoma and UM-UC-6 bladder cancer cells. These changes are mediated by H2O2, as co-expression of Catalase abrogates p130cas phosphorylation and its interaction with the adapter protein Crk. Importantly, we establish that the redox environment influence the localization of the tumor suppressor and phosphatase PTEN, in both redox-engineered and metastatic bladder cancer cells that display endogenous increases in H2O2. Importantly, PTEN oxidation leads to its dissociation from the plasma membrane. This indicates that oxidation of PTEN not only influences its activity, but also regulates its cellular localization, effectively removing it from its primary site of lipid phosphatase activity. These data introduce hitherto unappreciated paradigms whereby ROS can reciprocally regulate the cellular localization of pro- and anti-migratory signaling molecules, p130cas and PTEN, respectively. These data further confirm that altering antioxidant status and the intracellular ROS environment can have profound effects on pro-metastatic signaling pathways.

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Section: Discussionmentioning

confidence: 97%

Intracellular redox status controls membrane localization of pro- and anti-migratory signaling molecules

Hempel

Melendez

2014

Redox Biology

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“…1 As a consequence, 253J-BV cells displayed high redox-dependent MMP-9 and VEGF expression, and increased migration and invasion compared to the parental 253J line. 1,9 Moreover, we demonstrated that forced expression of Sod2 and increased steady-state ROS levels induce transcription of MMP-1 in fibrosarcoma HT-1080 cells. 24,25,46 In agreement with these findings, 253J-BV cells with higher steady-state redox status displayed significantly higher MMP-1 mRNA levels than 253J cells under normoxic (21% O 2 ) conditions in the present study (Fig.…”

Section: Resultsmentioning

confidence: 81%

“…1,9,45 Cells were pretreated in Dulbecco’s modified Eagle’s medium (DMEM) with 10% FBS and 2 mmol/L N-acetyl-L-cysteine (NAC; Sigma-Aldrich) for 18 hours, followed by the same treatments in serum-free media for the duration of the experiments. Cells were treated with H 2 O 2 (Sigma-Aldrich) in serum-free DMEM.…”

Section: Methodsmentioning

confidence: 99%

“…3,4,6–8 We and others have shown that steady-state increases in intracellular H 2 O 2 control metastatic behavior, including invasion and migration. 1,2,9, 10 These shifts in H 2 O 2 also drive the expression of pro-metastatic proteins such as Vascular Endothelial Growth Factor (VEGF) and Matrix Metalloproteinase (MMP) family members. 1,11 MMPs play an essential role in extracellular matrix (ECM) remodeling during morphogenesis, embryogenesis and wound healing, and their increased expression in cancer is associated with tumor angiogenesis, invasion and metastasis.…”

Section: Introductionmentioning

confidence: 99%

“…1,9 Given that metastatic tumor cells are often exposed to environmental conditions of low oxygen, we set out to investigate how increased steady-state ROS levels influence the response of metastatic tumor cells to hypoxia. Using a cell culture model of metastatic progression we found that an elevated steady-state redox milieu uniquely predisposes metastatic cancer cells to hypoxia-mediated MMP-1 regulation in a ROS-dependent manner.…”

Section: Introductionmentioning

confidence: 99%

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Regulation of MMP-1 expression in response to hypoxia is dependent on the intracellular redox status of metastatic bladder cancer cells

Shin

Dier

Melendez

et al. 2015

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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High steady-state reactive oxygen species (ROS) production has been implicated with metastatic disease progression. We provide new evidence that this increased intracellular ROS milieu uniquely predisposes metastatic tumor cells to hypoxia-mediated regulation of the matrix metalloproteinase MMP-1. Using a cell culture metastatic progression model we previous reported that steady-state intracellular H2O2 levels are elevated in highly metastatic 253J-BV bladder cancer cells compared to their non-metastatic 253J parental cells. 253J-BV cells display higher basal MMP-1 expression, which is further enhanced under hypoxic conditions (1% O2). This hypoxia-mediated MMP-1 increase was not observed in the non-metastatic 253J cells. Hypoxia-induced MMP-1 increases are accompanied by stabilization of hypoxia-inducible transcription factors (HIF)-1α and HIF-2α, and a rise in intracellular ROS in metastatic 253J-BV cells. RNA interference studies show that hypoxia-mediated MMP-1 expression is primarily dependent on the presence of HIF-2α. Further, hypoxia promotes migration and spheroid outgrowth of only the metastatic 253J-BV cells and not the parental 253J cells. The observed HIF stabilization, MMP-1 expression and migration under hypoxia are dependent on increases in intracellular ROS, as these effects are attenuated by treatment with the antioxidant N-acetyl-L-cysteine. These data show that ROS play an important role in hypoxia-mediated MMP-1 expression and that an elevated intracellular redox environment, as observed in metastasis, predisposes tumor cells to an enhanced hypoxic response. It further supports the notion that metastatic tumor cells are uniquely able to utilize intracellular increases in ROS to drive pro-metastatic signaling events and highlights the important interplay between ROS and hypoxia in malignancy.

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Dose‐Dependent Carbon‐Dot‐Induced ROS Promote Uveal Melanoma Cell Tumorigenicity via Activation of mTOR Signaling and Glutamine Metabolism

Ding

Chen

et al. 2021

Advanced Science

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Uveal melanoma (UM) is the most common intraocular malignant tumor in adults and has a low survival rate following metastasis; it is derived from melanocytes susceptible to reactive oxygen species (ROS). Carbon dot (Cdot) nanoparticles are a promising tool in cancer detection and therapy due to their unique photophysical properties, low cytotoxicity, and efficient ROS productivity. However, the effects of Cdots on tumor metabolism and growth are not well characterized. Here, the effects of Cdots on UM cell metabolomics, growth, invasiveness, and tumorigenicity are investigated in vitro and in vivo zebrafish and nude mouse xenograft model. Cdots dose-dependently increase ROS levels in UM cells. At Cdots concentrations below 100 µg mL −1 , Cdot-induced ROS promote UM cell growth, invasiveness, and tumorigenicity; at 200 µg mL −1 , UM cells undergo apoptosis. The addition of antioxidants reverses the protumorigenic effects of Cdots. Cdots at 25-100 µg mL −1 activate Akt/mammalian target of rapamycin (mTOR) signaling and enhance glutamine metabolism, generating a cascade that promotes UM cell growth. These results demonstrate that moderate, subapoptotic doses of Cdots can promote UM cell tumorigenicity. This study lays the foundation for the rational application of ROS-producing nanoparticles in tumor imaging and therapy.

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Acquisition of the Metastatic Phenotype Is Accompanied by H2O2-Dependent Activation of the p130Cas Signaling Complex

Cited by 27 publications

References 50 publications

Intracellular redox status controls membrane localization of pro- and anti-migratory signaling molecules

Intracellular redox status controls membrane localization of pro- and anti-migratory signaling molecules

Regulation of MMP-1 expression in response to hypoxia is dependent on the intracellular redox status of metastatic bladder cancer cells

Dose‐Dependent Carbon‐Dot‐Induced ROS Promote Uveal Melanoma Cell Tumorigenicity via Activation of mTOR Signaling and Glutamine Metabolism

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