Targeting MAPK Signaling in Cancer: Mechanisms of Drug Resistance and Sensitivity

Lee, Shannon; Rauch, Jens; Kölch, Walter

doi:10.3390/ijms21031102

Cited by 486 publications

(393 citation statements)

References 205 publications

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“…The three primary components of MAPKs are p38, JNK, and ERK; ERK is primarily involved in survival, whereas p38 and JNK are responsive to stress conditions, including the apoptotic phenotype [ 21 ]. In cancer cells, however, MAPK signaling cascades are dysregulated, owing to genetic mutations or environmental stimuli; hence, numerous studies have focused on developing therapeutic agents to restore the balance of MAPK function [ 22 ]. In this study, p38, though not JNK and ERK, was phosphorylated during CT-mediated HL-60 apoptosis.…”

Section: Discussionmentioning

confidence: 99%

1-Cinnamoyltrichilinin from Melia azedarach Causes Apoptosis through the p38 MAPK Pathway in HL-60 Human Leukemia Cells

Jeong

Park

Kim

et al. 2020

IJMS

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Acute myeloid leukemia (AML) is an aggressive type of human leukemia with a low survival rate, and its complete remission remains challenging. Although chemotherapy is the first-line treatment of AML, it exerts toxicity in noncancerous cells when used in high doses, thus necessitating the development of novel compounds with a high therapeutic window. This study aimed to investigate the anticancer effects of several compounds derived from the fruits of Melia azedarach (a tree with medicinal properties). Among them, 1-cinnamoyltrichilinin (CT) was found to strongly suppress the viability of HL-60 human leukemia cells. CT treatment induced apoptosis and increased nuclear fragmentation and fractional DNA content in HL-60 cells in a dose-dependent manner. CT induced phosphorylation of p38 mitogen-activated protein kinases (p38), though not of c-Jun N-terminal kinase (JNK) and extracellular signal-regulated kinase (ERK), and activated Bcl-2 family proteins towards the proapoptosis and cleavage of caspase-3 and poly (ADP-ribose) polymerase. Both CT-mediated apoptosis and apoptotic protein expression were reversed by treatment with the p38 inhibitor, thereby indicating the p38 pathway to be critical in CT-stimulated apoptosis. The results collectively indicated CT to suppress HL-60 survival by activating the p38 pathway and inducing apoptosis, hence being a novel potential therapeutic agent for AML.

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Section: Discussionmentioning

confidence: 99%

1-Cinnamoyltrichilinin from Melia azedarach Causes Apoptosis through the p38 MAPK Pathway in HL-60 Human Leukemia Cells

Jeong

Park

Kim

et al. 2020

IJMS

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“…medical therapies in tumor: for example, drugs targeting MAPK signaling in cancer (Lee et al, 2020), may also be effective in keloid treatment.…”

Section: Discussionmentioning

confidence: 99%

Single-cell RNA-seq reveals lineage-specific regulatory changes of fibroblasts and vascular endothelial cells in keloid

Liu

Chen

Yuan

et al. 2020

Preprint

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Keloid is a benign dermal fibrotic disorder with some features similar to malignant tumors such as hyper-proliferation, apoptosis resistance and invasion. keloid remains a therapeutic challenge in terms of high recurrence rate and lack of satisfactory medical therapies, which is partially due to the incomplete understanding of keloid pathogenesis. A thorough understanding of the cellular and molecular mechanism of keloid pathogenesis would facilitate the development of novel medical therapies for this disease. Here, we 2 / 37 performed single-cell RNA-seq of 28,064 cells from keloid skin tissue and adjacent relatively normal tissue. Unbiased clustering revealed substantial cellular heterogeneity of the keloid tissue, which included 21 cell clusters assigned to 11 cell lineages. Differential proportion analysis revealed significant expansion for fibroblasts and vascular endothelial cells in keloid compared with control, reflecting their strong association with keloid pathogenesis. We then identified five previously unrecognized subpopulations of keloid fibroblasts and four subpopulations of vascular endothelial cells. Comparative analyses were performed to identify the dysregulated pathways, regulators and ligand-receptor interactions for keloid fibroblasts and vascular endothelial cells, the two important cell lineages in keloid pathogenesis and for medical interventions. Our results highlight the roles of transforming growth factor beta and Eph-ephrin signaling pathways in both the aberrant fibrogenesis and angiogenesis of keloid. Critical regulators and signaling receptors implicated in the fibrogenesis of other fibrotic disorders, such as TWIST1, FOXO3, SMAD3 and EPHB2, ranked at the top in the regulatory network of keloidfibroblasts. In addition, tumor-related pathways such as negative regulation of PTEN transcription were found to be activated in keloid fibroblasts and vascular endothelial cells, which may be responsible for the malignant features of keloid. Our study put novel insights into the pathogenesis of keloid, and provided potential targets for medical therapies. Our dataset also constitutes a valuable resource for further investigations of the mechanism of keloid pathogenesis.

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“…Notably, we identi ed that the GRP75/HMGA1 axis plays an oncogenic role by activating JNK/c-JUN signaling. Various ndings have reported that activation of the JNK/c-JUN signaling pathway is closely correlated with cancer progression, including recurrence [37][38][39]. For instance, Jorgense et al…”

Section: Discussionmentioning

confidence: 99%

GRP75-upregulated HMGA1 Expression Promotes Stage I Lung Adenocarcinoma Progression by Activating the JNK/c-JUN Signaling Pathway

Qiao

Wang

et al. 2020

Preprint

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Background: Recurrence is a major challenge in early-stage lung adenocarcinoma (LUAD) treatment. However, the recurrence mechanism is still unclear, and no biomarkers can predict recurrence in early-stage LUAD. Here, we investigated the role and mechanism of high-mobility group AT-hook 1 (HMGA1) and glucose-regulated protein 75-kDa (GRP75) in stage I LUAD and evaluated their potential as biomarkers for predicting the recurrence and prognosis of stage I LUAD.Methods: A TCGA dataset was used to investigate the clinical significance of HMGA1 and GRP75 in early-stage LUAD. Western blotting and immunohistochemistry were used to measure protein expression levels. The biological functions of HMGA1 and GRP75 in LUAD were investigated both in vitro and in vivo through overexpression and knockdown experiments. The interaction and regulation between HMGA1 and GRP75 were evaluated with coimmunoprecipitation and ubiquitination assays. The downstream signaling pathway of the GRP75/HMGA1 axis was investigated by mRNA-sequencing analysis.Results: High expression of HMGA1 and GRP75 was associated with recurrence and a poor prognosis in stage I LUAD patients. In particular, HMGA1 had potential as an independent prognostic factor. Overexpression of GRP75 or HMGA1 promoted LUAD cell growth and metastasis, while silencing GRP75 or HMGA1 inhibited LUAD cell growth and metastasis. In vitro and clinical data showed that the expression level of GRP75 positively regulated HMGA1 in LUAD and that GRP75 played an HMGA1-dependent role. In addition, GRP75 prolonged the half-life of HMGA1 by inhibiting HMGA1 ubiquitination via direct binding to HMGA1. Finally, we demonstrated that the GRP75/HMGA1 axis played a role by activating JNK/c-JUN signaling in LUAD.Conclusions: The activation of GRP75/HMGA1/JNK/c-JUN signaling is an important mechanism that promotes the progression of stage I LUAD, and a high level of HMGA1 is a novel biomarker for predicting recurrence and prognosis in patients with stage I LUAD.

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Targeting MAPK Signaling in Cancer: Mechanisms of Drug Resistance and Sensitivity

Cited by 486 publications

References 205 publications

1-Cinnamoyltrichilinin from Melia azedarach Causes Apoptosis through the p38 MAPK Pathway in HL-60 Human Leukemia Cells

1-Cinnamoyltrichilinin from Melia azedarach Causes Apoptosis through the p38 MAPK Pathway in HL-60 Human Leukemia Cells

Single-cell RNA-seq reveals lineage-specific regulatory changes of fibroblasts and vascular endothelial cells in keloid

GRP75-upregulated HMGA1 Expression Promotes Stage I Lung Adenocarcinoma Progression by Activating the JNK/c-JUN Signaling Pathway

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