Role of p38 MAP Kinase Signal Transduction in Solid Tumors

Koul, Hari K.; Pal, Mintu; Koul, Sweaty

doi:10.1177/1947601913507951

Cited by 426 publications

(345 citation statements)

References 255 publications

(306 reference statements)

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“…However, previous studies have suggested an opposite role of p38 MAPK in mediating cell apoptosis and growth inhibition, which indicated that p38 MAPK serves a dual role as a regulator of cell behavior (28,29). In the present study, it was observed that emodin could promote the phosphorylation of p38, indicating that the p38 MAPK signaling pathway may exert a function in response to the type of stimulus and in a cell type specific manner.…”

Section: Discussionsupporting

confidence: 51%

Emodin inhibits migration and invasion of MHCC-97H human hepatocellular carcinoma cells

Lin

Zhong

Liang

et al. 2016

Experimental and Therapeutic Medicine

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Abstract. Emodin, an anthraquinone derivative from the root and rhizome of Rheum palmatum L., was found to have antitumor effects in different types of cancer by regulating multi-molecular targets. The aim of the present study was to explore the effect of emodin on the migration and invasion of MHCC-97H human hepatocellular carcinoma cells and the underlying molecular mechanisms. Firstly, it was demonstrated that emodin can inhibit cell proliferation and induce apoptosis of cells in a time-and dose-dependent manner, using a MTT assay and flow cytometry, respectively. However, when emodin concentration was <50 µmol/l, it had little effect on the inhibition of proliferation or the induction of apoptosis. Then, it was observed that emodin can significantly suppress cell migration and invasion with a treatment dose <50 µmol/l compared with the control (P<0.05), which was not attributed to a decrease in cell number. Further study demonstrated that emodin significantly suppressed the expression levels of matrix metalloproteinase (MMP)-2 and MMP-9 compared with the control, which may be mediated by the activation of the p38 mitogen-activated protein kinases (MAPK) signaling pathway and suppression of extracellular signal regulated kinase (ERK)/MAPK and phosphatidylinositol 3-kinase/Akt signaling pathways. Therefore, the present study, for the first time, used MHCC-97H cells, which have the high potential of malignant invasion, to demonstrate that emodin may inhibit cell migration and invasion. IntroductionHepatocellular carcinoma (HCC) is one of the most frequent malignancies worldwide, representing the fifth most common cause of cancer in men and the seventh in women, and the third most frequent cause of cancer-related mortality (1-3). Globally, there are ~750,000 new cases of liver cancer reported per year (4). Although surgical resection provides better results in patients with HCC in early stages, the long-term prognosis remains unsatisfactory because many patients are diagnosed at the advanced stage, and tumors have an inherent capacity for invasiveness and metastasis (5,6). At present, chemotherapy is commonly used in the treatment of metastatic HCC. However, this treatment remains ineffective due to its toxicity to normal cells and the rapid development of resistance. Therefore, to further explore the biology of metastasis and develop novel therapeutics that specifically target metastasis and metastatic progression are required (7,8).Increasing attention has been paid to drugs among traditional Chinese medicines, since these materials typically share high safety profiles and can effectively prevent and control metastasis (9,10). Rheum palmatum L. is a plant that has been widely used in Chinese medicine as a laxative for thousands of years. Emodin is an anthraquinone derivative from its root and rhizome (11). It has been reported that emodin possesses a number of biological properties such as anti-inflammatory, antiviral and anti-proliferative effects (12). In the context of cancer, several studies have indicated...

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Section: Discussionsupporting

confidence: 51%

Emodin inhibits migration and invasion of MHCC-97H human hepatocellular carcinoma cells

Lin

Zhong

Liang

et al. 2016

Experimental and Therapeutic Medicine

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“…Vitamin D 3 exhibits several antiinflammatory effects, including inhibition of p38 stress kinase signaling and the subsequent production of proinflammatory cytokines (14). P38, a member of the MAPK family, has been reported to play a key role in the malignant transformation and is required for the invasive capacity of human hepatocellular carcinoma and HNSCC cell lines (40,41). The ability of calcitriol to reduce the production of proinflammatory cytokines, such as IL6, by inhibiting p38 signaling has been demonstrated in cancer cells (42).…”

Section: Discussionmentioning

confidence: 99%

1α,25-Dihydroxyvitamin D3 Inhibits Esophageal Squamous Cell Carcinoma Progression by Reducing IL6 Signaling

Chen

Hsieh

et al. 2015

Molecular Cancer Therapeutics

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The aim of this study was to highlight the role of 1a,25-dihydroxyvitamin D3 (calcitriol) in esophageal squamous cell carcinoma (SCC). The human esophageal SCC cell lines CE81T and TE2 were selected for cellular and animal experiments to investigate the changes in tumor behavior after calcitriol supplementation and the underlying mechanisms. Moreover, we evaluated the relationship between calcitriol supplementation, myeloid-derived suppressor cell (MDSC) recruitment, IL6 levels, and tumor progression by a 4-nitroquinoline 1-oxide (4-NQO)-induced esophageal tumor animal model. In this study, we demonstrated that calcitriol supplementation inhibited aggressive tumor behavior both in vitro and in vivo. The underlying changes included increased cell death, a lower degree of epithelial-mesenchymal transition, and inhibited IL6 signaling. In the 4-NQOinduced esophageal tumor animal model, increased IL6 and MDSC recruitment were linked with invasive esophageal tumors. Supplementation with calcitriol attenuated the level of IL6, the induction of MDSCs, and the incidence of 4-NQO-induced invasive tumors. Moreover, the IL6-induced changes in C57 mice, including augmented MDSC recruitment, increased levels of ROS and p-Stat3 in MDSCs, and higher suppressive function of MDSCs in T-cell proliferation, which were abrogated by calcitriol supplementation. On the basis of our results, we concluded that calcitriol abrogated the IL6-induced aggressive tumor behavior and MDSC recruitment to inhibit esophageal tumor promotion. Therefore, we suggest that supplementation with vitamin D 3 may be a promising strategy for the prevention and treatment of esophageal SCC.

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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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Role of p38 MAP Kinase Signal Transduction in Solid Tumors

Cited by 426 publications

References 255 publications

Emodin inhibits migration and invasion of MHCC-97H human hepatocellular carcinoma cells

Emodin inhibits migration and invasion of MHCC-97H human hepatocellular carcinoma cells

1α,25-Dihydroxyvitamin D3 Inhibits Esophageal Squamous Cell Carcinoma Progression by Reducing IL6 Signaling

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

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