Activation of JNK and p38 MAPK Mediated by ZDHHC17 Drives Glioblastoma Multiforme Development and Malignant Progression

Chen, Xueran; Hao, Aijun; Li, Xian; Ye, Kaiqin; Zhao, Chenggang; Yang, Haoran; Ma, Huihui; Hu, Lei; Zhao, Zhiyang; Hu, Lizhu; Ye, Fang; Sun, Qiuyan; Zhang, Huaman; Wang, Hongzhi; Yao, Xuebiao; Fang, Zhiyou

doi:10.7150/thno.40076

Cited by 59 publications

(44 citation statements)

References 48 publications

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“…Infections by many viruses, such as HCV 7 , influenza virus 8 , enterovirus 71 (EV71) 9 , human immunodeficiency virus (HIV) 10 , dengue virus (DENV) 11 , and hepatitis B virus (HBV) 12 , can activate p38 MAP kinases. There are four p38 kinase members in the mitogen-activated protein (MAP) family in mammals, p38α, p38β, p38γ and p38δ, which play crucial roles in many biological processes in response to extracellular stimuli that mediate a variety of biological processes, such as inflammation, cell proliferation, apoptosis and differentiation, aging and tumorigenesis 13 - 15 . P38 MAPK is prototypically modulated by MAP3K, MAPKK, and MAPK in the classical pathway 16 - 18 .…”

Section: Introductionmentioning

confidence: 99%

Virus-induced p38 MAPK activation facilitates viral infection

et al. 2020

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Rationale: Many viral infections are known to activate the p38 mitogen-activated protein kinase (MAPK) signaling pathway. However, the role of p38 activation in viral infection and the underlying mechanism remain unclear. The role of virus-hijacked p38 MAPK activation in viral infection was investigated in this study. Methods: The correlation of hepatitis C virus (HCV) infection and p38 activation was studied in patient tissues and primary human hepatocytes (PHHs) by immunohistochemistry and western blotting. Coimmunoprecipitation, GST pulldown and confocal microscopy were used to investigate the interaction of p38α and the HCV core protein. In vitro kinase assays and mass spectrometry were used to analyze the phosphorylation of the HCV core protein. Plaque assays, quantitative real time PCR (qRT-PCR), western blotting, siRNA and CRISPR/Cas9 were used to determine the effect of p38 activation on viral replication. Results: HCV infection was associated with p38 activation in clinical samples. HCV infection increased p38 phosphorylation by triggering the interaction of p38α and TGF-β activated kinase 1 (MAP3K7) binding protein 1 (TAB1). TAB1-mediated p38α activation facilitated HCV replication, and pharmaceutical inhibition of p38α activation by SB203580 suppressed HCV infection at the viral assembly step. Activated p38α interacted with the N-terminal region of the HCV core protein and subsequently phosphorylated the HCV core protein, which promoted HCV core protein oligomerization, an essential step for viral assembly. As expected, SB203580 or the HCV core protein N-terminal peptide (CN-peptide) disrupted the p38α-HCV core protein interaction, efficiently impaired HCV assembly and impeded normal HCV replication in both cultured cells and primary human hepatocytes. Similarly, severe fever with thrombocytopenia syndrome virus (SFTSV), herpes simplex virus type 1 (HSV-1) or severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection also activated p38 MAPK. Most importantly, pharmacological blockage of p38 activation by SB203580 effectively inhibited SFTSV, HSV-1 and SARS-CoV-2. Conclusion: Our study shows that virus-hijacked p38 activation is a key event for viral replication and that pharmacological blockage of p38 activation is an antiviral strategy.

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Section: Introductionmentioning

confidence: 99%

Virus-induced p38 MAPK activation facilitates viral infection

et al. 2020

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“…The effect of capsaicin on the p38 signaling pathway is of particular interest, as this pathway is critical to cancer progression and metastasis 32 - 34 . MKK3 and MKK6 are kinases upstream of p38, and are involved in cell differentiation, division, migration, apoptosis and stress responses 35 .…”

Section: Introductionmentioning

confidence: 99%

Therapeutic potential of targeting MKK3-p38 axis with Capsaicin for Nasopharyngeal Carcinoma

Chiang¹,

Zhang²,

Wang³

et al. 2020

Theranostics

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Background: Capsaicin is an active compound found in plants of the Capsicum genus; it has a range of therapeutic benefits, including anti-tumor effects. Here we aimed to delineate the inhibitory effects of capsaicin on nasopharyngeal carcinoma (NPC). Methods: The anti-cancer effects of capsaicin were confirmed in NPC cell lines and xenograft mouse models, using CCK-8, clonogenic, wound-healing, transwell migration and invasion assays. Co-immunoprecipitation, western blotting and pull-down assays were used to determine the effects of capsaicin on the MKK3-p38 axis. Cell proliferation and EMT marker expression were monitored in MKK3 knockdown (KD) or over-expression NPC cell lines treated with or without capsaicin. Finally, immunohistochemistry was performed on NPC specimens from NPC patients (n = 132) and the clinical relevance was analyzed. Results: Capsaicin inhibited cell proliferation, mobility and promoted apoptosis in NPC cells. Then we found that capsaicin directly targets p38 for dephosphorylation. As such, MKK3-induced p38 activation was inhibited by capsaicin. Furthermore, we found that capsaicin-induced inhibition of cell motility was mediated by fucokinase. Xenograft models demonstrated the inhibitory effects of capsaicin treatment on NPC tumor growth in vivo , and analysis of clinical NPC samples confirmed that MKK3 phosphorylation was associated with NPC tumor growth and lymphoid node metastasis. Conclusions: The MKK3-p38 axis represents a potential therapeutic target for capsaicin. MKK3 phosphorylation might serve as a biomarker to identify NPC patients most likely to benefit from adjunctive capsaicin treatment.

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“…In addition, the gene encoding ZDHHC17 is located in the chromosomal region containing a potential oncogene of glioma. ZDHHC17 protein can interact with MAP 2K4 to regulate the development and progression of malignant glioma and stimulate JNK/p38 [44]. In this study, we investigated the association between the DHHC family of proteins and local anesthetics in gliomas and found that ZDHHC15 was significantly downregulated in GSCs after treatment with prilocaine, procaine, lidocaine, or ropivacaine.…”

Section: Discussionmentioning

confidence: 93%

Local anesthetics impair the growth and self-renewal of glioblastoma stem cells by inhibiting ZDHHC15-mediated GP130 palmitoylation

et al. 2021

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Background A large number of preclinical studies have shown that local anesthetics have a direct inhibitory effect on tumor biological activities, including cell survival, proliferation, migration, and invasion. There are few studies on the role of local anesthetics in cancer stem cells. This study aimed to determine the possible role of local anesthetics in glioblastoma stem cell (GSC) self-renewal and the underlying molecular mechanisms. Methods The effects of local anesthetics in GSCs were investigated through in vitro and in vivo assays (i.e., Cell Counting Kit 8, spheroidal formation assay, double immunofluorescence, western blot, and xenograft model). The acyl-biotin exchange method (ABE) assay was identified proteins that are S-acylated by zinc finger Asp-His-His-Cys-type palmitoyltransferase 15 (ZDHHC15). Western blot, co-immunoprecipitation, and liquid chromatograph mass spectrometer-mass spectrometry assays were used to explore the mechanisms of ZDHHC15 in effects of local anesthetics in GSCs. Results In this study, we identified a novel mechanism through which local anesthetics can damage the malignant phenotype of glioma. We found that local anesthetics prilocaine, lidocaine, procaine, and ropivacaine can impair the survival and self-renewal of GSCs, especially the classic glioblastoma subtype. These findings suggest that local anesthetics may weaken ZDHHC15 transcripts and decrease GP130 palmitoylation levels and membrane localization, thus inhibiting the activation of IL-6/STAT3 signaling. Conclusions In conclusion, our work emphasizes that ZDHHC15 is a candidate therapeutic target, and local anesthetics are potential therapeutic options for glioblastoma.

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Activation of JNK and p38 MAPK Mediated by ZDHHC17 Drives Glioblastoma Multiforme Development and Malignant Progression

Cited by 59 publications

References 48 publications

Virus-induced p38 MAPK activation facilitates viral infection

Virus-induced p38 MAPK activation facilitates viral infection

Therapeutic potential of targeting MKK3-p38 axis with Capsaicin for Nasopharyngeal Carcinoma

Local anesthetics impair the growth and self-renewal of glioblastoma stem cells by inhibiting ZDHHC15-mediated GP130 palmitoylation

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