p38 MAPK: A dual role in hepatocyte proliferation through reactive oxygen species

Tormos, Ana M.; Taléns‐Visconti, Raquel; Nebreda, Ángel R.; Sastre, Juan

doi:10.3109/10715762.2013.821200

Cited by 91 publications

(74 citation statements)

References 155 publications

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“…Importantly, reconstitution of p38 activity by ectopic expression of constitutively active MKK3(EE) in Ubc13-deficient BCa cells restores their metastatic potential. Involvement of p38 MAPK signaling in cancer development, progression, and metastasis has been demonstrated previously (45)(46)(47)(48). The p38 MAPK was suggested to overcome ERK signaling to promote survival of dormant cancer cells through activation of the unfolded protein response (49)(50)(51), as well as various steps in the process of invasion and metastasis (20).…”

Section: Discussionmentioning

confidence: 81%

Ubiquitin-conjugating enzyme Ubc13 controls breast cancer metastasis through a TAK1-p38 MAP kinase cascade

Zhang

Font-Burgada

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Metastatic spread is the leading cause of cancer mortality. Breast cancer (BCa) metastatic recurrence can happen years after removal of the primary tumor. Here we show that Ubc13, an E2 enzyme that catalyzes K63-linked protein polyubiquitination, is largely dispensable for primary mammary tumor growth but is required for metastatic spread and lung colonization by BCa cells. Loss of Ubc13 inhibited BCa growth and survival only at metastatic sites. Ubc13 was dispensable for transforming growth factor β (TGFβ)-induced SMAD activation but was required for activation of non-SMAD signaling via TGFβ-activating kinase 1 (TAK1) and p38, whose activity controls expression of numerous metastasis promoting genes. p38 activation restored metastatic activity to Ubc13-deficient cells, and its pharmacological inhibition attenuated BCa metastasis in mice, suggesting it is a therapeutic option for metastatic BCa.ubiquitination-mediated signaling | pre-clinical studies B reast cancer (BCa) is the leading invasive cancer among women worldwide. BCa-related mortality is usually caused by distant metastases rather than primary tumors (1, 2). The spread of cancer cells from primary tumors to distant organs, termed metastasis, is a multistep process in which cancer cells must (i) invade through the extracellular matrix (ECM), (ii) disseminate into the bloodstream, (iii) survive in the circulation, and (iv) extravasate and successfully colonize distant sites (3). Conventional therapeutic strategies have limited success in preventing and treating metastatic cancer, and BCa metastases can recur many years after removal of the primary tumor. This phenomenon could be due to the complex nature of metastasis itself, and, more realistically, the limitation of current treatments that are effective against primary BCa, i.e., surgical removal and localized radiotherapy, but do little to prevent metastatic recurrence. Even chemotherapy is not very effective against metastatic tumors (4). Unfortunately, the pharmaceutical industry has been reluctant to conduct metastasis prevention trials on patients with early stage cancer using survival and reduction of metastatic load as end points, because such studies are lengthy and require a large number of patients with otherwise relatively good survival prospects (4). Consequently, the development of agents that prevent metastasis from occurring and trigger regression of established metastatic lesions is an urgent unmet need.It was reported that expression of the ubiquitin conjugating enzyme (E2) Ubc13 is up-regulated in metastatic BCa (5). Ubc13, which heterodimerizes with Uev1a, catalyzes formation of lysine 63 (K63)-linked polyubiquitin chains, which control protein-protein interactions involved in DNA damage repair and protein kinase activation (6, 7). In certain immune cells, Ubc13 is required for IκB kinase (IKK)-nuclear factor κB (NF-κB) activation, but a more ubiquitous role for Ubc13 was observed in the activation of MAPK signaling (8-11). We found that Ubc13 is required for activation of mitogen-a...

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Section: Discussionmentioning

confidence: 81%

Ubiquitin-conjugating enzyme Ubc13 controls breast cancer metastasis through a TAK1-p38 MAP kinase cascade

Zhang

Font-Burgada

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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“…As demonstrated by the ABTS assay (Figure 4b), 100 μg/ml RPE exhibited over 90% ABTS radical scavenging activity; this was comparable to that of 10 μg/ml vitamin C (Figure 4a). As we described in the introduction section, aberrant ROS production can accelerate DNA damage and activate inflammatory signaling pathways (Chen et al., 2006; Tormos et al., 2013). Therefore, we hypothesized that suppression of MAPK signaling pathway is mediated by antioxidant activities of RPE.…”

Section: Discussionmentioning

confidence: 99%

“…Previous studies have demonstrated that ROS activates inflammatory signaling pathways (Chen et al., 2006; Tormos, Talens‐Visconti, Nebreda, & Sastre, 2013). We also found that N ‐acetyl cysteine (NAC, a ROS scavenger) drastically inhibited sUV‐induced matrix metalloprotein‐1 (MMP‐1) expression (data not shown) and siRNA of p47 phox , a subunit of NADPH oxidase (NOX); as a result, reduction of EGFR transactivation in NADPH oxidase was observed (Chen et al., 2006).…”

Section: Introductionmentioning

confidence: 99%

Skin anti‐inflammatory activity of rose petal extract (Rosa gallica) through reduction of MAPK signaling pathway

Lee

Nam

Lee

et al. 2018

Food Science & Nutrition

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The aim of this study was to investigate the skin anti‐inflammatory activity of rose petal extract (RPE) and the mechanisms underlying this phenomenon. Recently, flowers have been considered as dietary resources owing to their biological activities, such as inhibition of nephritis and hemorrhoids. The Rosa plant exerts various biological functions, including antioxidant and anti‐microbiological activities. Herein, we confirmed the skin anti‐inflammatory activity of RPE upon solar UV (sUV) exposure. RPE reduced sUV‐induced COX‐2 expression as well as expressions of several cytokines. Activation of MKK4‐JNK, MEK‐ERK, and MKK3‐p38 signaling pathways, which are associated with cytokine production, was also attenuated by RPE treatment. We hypothesized these RPE‐induced changes are because of its antioxidant activity, because RPE displayed drastic radical scavenging and oxygen radical absorbance capacity (ORAC). Furthermore, high anthocyanins, polyphenols, and flavonoids contents were found in RPE. Hence, these results indicated the skin anti‐inflammatory activity of RPE is because of antioxidant activity.

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“…55 The ultimate effect of p38 MAPK activation depends on the type of stimulus in a cell-type-specific manner. [56][57][58] To further explore the role of p38 activation in response to VX680 treatment, we treated cells with BIRB796. BIRB796 is a novel p38 MAPK inhibitor that inhibits all p38 MAPK isoforms in vitro and vivo.…”

Section: Discussionmentioning

confidence: 99%

The p38 MAPK inhibitor BIRB796 enhances the antitumor effects of VX680 in cervical cancer

Jin

Zhang

et al. 2016

Cancer Biology & Therapy

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VX680 is a potent and selective inhibitor that targets the Aurora kinase family. The p38 mitogen-activated protein kinase (MAPK) regulates a large number of cellular pathways and plays an important role in the regulation of cell survival and apoptosis. This study aimed to evaluate the effect of VX680 on cervical cancer cells and investigate whether the effects on apoptosis are enhanced by the ablation of p38 MAPK activation. The results suggested that VX680 inhibited the proliferation of cervical cancer cells by causing G2/M phase arrest and endoreduplication and that the apoptotic effect was attenuated by the activation of p38 MAPK. However, the addition of BIRB796, which is an important p38 MAPK inhibitor, effectively eliminated the expression of p-p38 and hence significantly enhanced the cell death induced by VX680 in vitro. Further study demonstrated that BIRB796 cooperated with VX680 to suppress cervical cancer cell growth in a mouse xenograft model. Taken together, our results demonstrated that VX680 induced cell cycle arrest and endoreduplication in human cervical cancer cells. Combined treatment with VX680 and BIRB796 synergistically inhibited tumor growth both in vitro and in vivo. Dual blockade of Aurora kinases and p38 MAPK is therefore a promising strategy for cervical cancer treatment.

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p38 MAPK: A dual role in hepatocyte proliferation through reactive oxygen species

Cited by 91 publications

References 155 publications

Ubiquitin-conjugating enzyme Ubc13 controls breast cancer metastasis through a TAK1-p38 MAP kinase cascade

Ubiquitin-conjugating enzyme Ubc13 controls breast cancer metastasis through a TAK1-p38 MAP kinase cascade

Skin anti‐inflammatory activity of rose petal extract (Rosa gallica) through reduction of MAPK signaling pathway

The p38 MAPK inhibitor BIRB796 enhances the antitumor effects of VX680 in cervical cancer

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