Isoform-specific and cell/tissue-dependent effects of p38 MAPKs in regulating inflammation and inflammation-associated oncogenesis

Qin, Jian‐Zhong; Xiao, Hong; Qi, Xiaomei; Chen, Guan

doi:10.31083/j.fbl2701031

Cited by 10 publications

(8 citation statements)

References 84 publications

(152 reference statements)

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“…Although p38γ MAPK has been less investigated, it has unique functions particularly in the regulation of cell cycle progression, mobility, migration/invasion, cancer stem cells (CSCs), and epithelial-mesenchymal transition (EMT) ( 10 , 11 ). The activation and over-expression of p38γ MAPK is associated with malignant tumors ( 11 , 12 ). We have previously showed that alcohol activated p38γ MAPK, which may lead to increased CSCs and metastasis of breast cancer cells ( 7 – 9 ).…”

Section: Introductionmentioning

confidence: 99%

Pirfenidone ameliorates alcohol-induced promotion of breast cancer in mice

Li,

Xu,

Chen

et al. 2024

Front. Oncol.

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PurposeAlcohol consumption increases the risk of breast cancer and promotes cancer progression. Alcohol exposure could affect both processes of the mammary carcinogenesis, namely, the cell transformation and onset of tumorigenesis as well as cancer aggressiveness including metastasis and drug resistance/recurrence. However, the cellular and molecular mechanisms underlying alcohol tumor promotion remain unclear. There are four members of the mammalian p38 mitogen-activated protein kinase (MAPK) family, namely, p38α, p38β, p38γ and p38δ. We have previously demonstrated alcohol exposure selectively activated p38γ MAPK in breast cancer cells in vitro and in vivo. Pirfenidone (PFD), an antifibrotic compound approved for the treatment of idiopathic pulmonary fibrosis, is also a pharmacological inhibitor of p38γ MAPK. This study aimed to determine whether PFD is useful to inhibit alcohol-induced promotion of breast cancer.MethodsFemale adolescent (5 weeks) MMTV-Wnt1 mice were exposed to alcohol with a liquid diet containing 6.7% ethanol. Some mice received intraperitoneal (IP) injection of PFD (100 mg/kg) every other day. After that, the effects of alcohol and PFD on mammary tumorigenesis and metastasis were examined.ResultsAlcohol promoted the progression of mammary tumors in adolescent MMTV-Wnt1 mice. Treatment of PFD blocked tumor growth and alcohol-promoted metastasis. It also significantly inhibited alcohol-induced tumorsphere formation and cancer stem cell (CSC) population.ConclusionPFD inhibited mammary tumor growth and alcohol-promoted metastasis. Since PFD is an FDA-approved drug, the current findings may be helpful to re-purpose its application in treating aggressive breast cancer and alcohol-promoted mammary tumor progression.

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Section: Introductionmentioning

confidence: 99%

Pirfenidone ameliorates alcohol-induced promotion of breast cancer in mice

Li,

Xu,

Chen

et al. 2024

Front. Oncol.

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“…[ 16 ] Moreover, the mitogen‐activated protein kinase (MAPK) cascade, as a conserved signaling module downstream of receptors/sensors, has been implicated as playing a critical regulatory function in the generation of proinflammatory cytokine. [ 17 ] Extracellular regulated protein kinase (ERK), c‐Jun N‐terminal kinase (JNK), and p38 mitogen‐activated protein kinase (p38) are the major kinases in the MAPK signaling pathway. Activation of the MAPK/ERK/JNK/P38 pathway is accompanied by the activation of inflammatory signaling pathways, such as nuclear factor kappa‐B (NF‐κB) and B‐cell lymphoma‐2 (Bcl‐2), which mediate the expression of inducible nitric oxide synthase (iNOS), IL‐1β, tumor necrosis factor‐α (TNF‐α), and other markers of inflammation, further exacerbating the development of UC.…”

Section: Introductionmentioning

confidence: 99%

Polyphenol Extracts from Ziziphus jujuba Mill. “Junzao” Attenuates Ulcerative Colitis by Inhibiting the NLRP3 and MAPKs Signaling Pathways and Regulating Gut Microbiota Homeostasis in Mice

Wei,

Ma,

Yang

et al. 2024

Molecular Nutrition Food Res

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ScopePolyphenols are the major active substances in red jujube fruit, and their anti‐inflammatory and antioxidant activities suggest their potential utility in the prevention of ulcerative colitis (UC).Methods and resultsIn this study, the effect of polyphenol extracts from red jujube (Ziziphus jujuba Mill. “Junzao”) (PERJ) on the dextron sulfate sodium (DSS)‐induced UC mice is investigated. The result shows that PERJ effectively improves clinical symptoms, including food and water intake, the disease activity insex (DAI) and spleen index, and routine blood levels, and alleviates the shortening of the colon, in mice with DSS‐induced UC. Meanwhile, PERJ remarkably decreases the expression of proinflammatory factors. Moreover, PERJ repairs intestinal barrier damage by increasing the expression level of mucin 2 and mucin 3, and the result is also confirmed in the histological assessment. Besides, the expression levels of Nod‐like receptor family pyrin domain‐containing 3 (NLRP3) and mitogen‐activated protein kinase cascade (MAPKs) signaling pathway‐related proteins are inhibited by the PERJ administration. Finally, 16S rRNA sequencing analyses reveal that PERJ reverses intestinal microbiota dysbiosis by enhancing the abundance of Firmicutes and decreasing that of Proteobacteria and Bacteroidetes.ConclusionPERJ probably inhibits the development of UC by suppressing the NLRP3 and MAPKs signaling pathways and regulating gut microbiota homeostasis, and can be considered as a potential resource for preventing UC.

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“…Although these isoform-specific activations are important for different cellular outcomes, the mechanisms involved are largely unknown [ 2 , 5 , 6 ]. Isoform-specific and tissue-dependent effects of p38 MAPKs in inflammation and inflammation-associated oncogenesis have been recently reviewed [ 7 ]. This manuscript will focus on recent discoveries regarding p38γ inflammatory and metabolic signaling in physiology and diseases.…”

Section: Introductionmentioning

confidence: 99%

p38γ MAPK Inflammatory and Metabolic Signaling in Physiology and Disease

Chen

2023

Cells

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p38γ MAPK (also called ERK6 or SAPK3) is a family member of stress-activated MAPKs and has common and specific roles as compared to other p38 proteins in signal transduction. Recent studies showed that, in addition to inflammation, p38γ metabolic signaling is involved in physiological exercise and in pathogenesis of cancer, diabetes, and Alzheimer’s disease, indicating its potential as a therapeutic target. p38γphosphorylates at least 19 substrates through which p38γ activity is further modified to regulate life-important cellular processes such as proliferation, differentiation, cell death, and transformation, thereby impacting biological outcomes of p38γ-driven pathogenesis. P38γ signaling is characterized by its unique reciprocal regulation with its specific phosphatase PTPH1 and by its direct binding to promoter DNAs, leading to transcriptional activation of targets including cancer-like stem cell drivers. This paper will review recent findings about p38γ inflammation and metabolic signaling in physiology and diseases. Moreover, we will discuss the progress in the development of p38γ-specific pharmacological inhibitors for therapeutic intervention in disease prevention and treatment by targeting the p38γ signaling network.

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Isoform-specific and cell/tissue-dependent effects of p38 MAPKs in regulating inflammation and inflammation-associated oncogenesis

Cited by 10 publications

References 84 publications

Pirfenidone ameliorates alcohol-induced promotion of breast cancer in mice

Pirfenidone ameliorates alcohol-induced promotion of breast cancer in mice

Polyphenol Extracts from Ziziphus jujuba Mill. “Junzao” Attenuates Ulcerative Colitis by Inhibiting the NLRP3 and MAPKs Signaling Pathways and Regulating Gut Microbiota Homeostasis in Mice

p38γ MAPK Inflammatory and Metabolic Signaling in Physiology and Disease

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